Arylamides

ABSTRACT

The present invention relates to compounds, to processes for preparing them, to pharmaceutical compositions comprising them, and to their use in the therapy and/or prophylaxis of diseases in people or animals, especially diseases of bacterial infection.

The present invention relates to compounds, to processes for preparingthem, to pharmaceutical compositions comprising them, and to their usein the therapy and/or prophylaxis of diseases in people or animals,especially diseases of bacterial infection.

The natural substances moiramide B (R^(a)=hydrogen, R^(b)=methyl) andandrimid (R^(a)=hydrogen, R^(b)=propenyl) have been described as havingantibacterial activity, whereas moiramide C (R^(a)=hydroxyl,R^(b)=propenyl) is inactive. (A. Fredenhagen, S. Y. Tamura, P. T. M.Kenny, H. Komura, Y. Naya, K. Nakanishi, J. Am. Chem. Soc., 1987, 109,4409-4411; J. Needham, M. T. Kelly, M. Ishige, R. J. Andersen, J. Org.Chem., 1994, 59, 2058-2063; M. P. Singh, M. J. Mroczenski-Wildey, D. A.Steinberg, R. J. Andersen, W. M. Maiese, M. Greenstein, J. Antibiot.,1997, 50(3), 270-273). The isolation and antibacterial activity ofandrimid is also desccribed in EP-A-250 115. JP 01301657 describes theuse of andrimid and certain amide-type derivatives as agrochemicalantibiotics.

The synthesis of andrimid is described in A. V. Rama Rao, A. K. Singh,Ch. V. N. S. Varaprasad, Tetrahedron Letters, 1991, 32, 4393-4396, thatof moiramide B and andrimid in S. G. Davies, D. J. Dixon, J. Chem. Soc.,Perkin Trans. 1, 1998, 2635-2643.

Although antibacterial products with different structures are on themarket, a regular possibility is the development of resistance. Newproducts for improved and effective therapy are therefore desirable.

It is an object of the present invention, therefore, to provide new andalternative compounds having equal or improved antibacterial action fortreating bacterial diseases in people and animals.

Surprisingly it has been found that derivatives of this class ofcompound in which the beta-phenylalanine amide group is replaced by aheteroaromatic or substituted aromatic amide have antibacterialactivity.

The present invention provides compounds of the formula

in which

-   R¹ is heteroaryl,    -   where heteroaryl can be substituted by 0, 1, 2 or 3 substituents        R¹⁻¹, the substituents R¹⁻¹ being selected independently of one        another from the group consisting of halogen, alkyl, nitro,        amino, alkylamino, cyano, trifluoromethyl, cycloalkyl,        heterocyclyl, aryl, heteroaryl, hydroxyl, alkoxy, aryloxy,        benzyloxy, carboxyl, alkoxycarbonyl, aminocarbonyl,        alkylcarbonylamino, alkylaminocarbonyl and aminosulfonyl,        or-   R¹ is aryl,    -   where aryl is substituted by 1, 2 or 3 substituents R¹⁻², the        substituents R¹⁻² being selected independently of one another        from the group consisting of halogen, alkyl, nitro, amino,        alkylamino, cyano, trifluoromethyl, cycloalkyl, heterocyclyl,        aryl, heteroaryl, hydroxyl, alkoxy, aryloxy, benzyloxy,        carboxyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonylamino,        arylcarbonylamino, alkylaminocarbonyl and aminosulfonyl,    -   or    -   two substituents R¹⁻², together with the carbon atoms to which        they are attached, form a cycloalkyl or heterocyclyl which can        be substituted by 0, 1 or 2 substituents R¹⁻²⁻¹, the        substituents R¹⁻²⁻¹ being selected independently of one another        from the group consisting of halogen, nitro, amino,        trifluoromethyl, hydroxyl, alkyl and alkoxy,-   R² is hydrogen or methyl,-   R³ is hydrogen, hydroxyl, amino, C₁-C₃ alkyl, benzyl, C₁-C₃ alkoxy,    benzyloxy, C₁-C₃ alkylamino, C₁-C₃ alkylcarbonylamino,    phenylcarbonylamino or benzylcarbonylamino,-   R⁴ is hydrogen or C₁-C₃ alkyl,-   R⁵ is halogen, trifluoromethyl, trifluoromethoxy, nitro, amino,    alkylamino, hydroxyl, alkyl, alkoxy, carboxyl, alkoxycarbonyl,    aminocarbonyl, alkylaminocarbonyl, aryl or heteroaryl,    -   or    -   two substituents R⁵ together with the carbon atoms to which they        are attached form a cycloalkyl or heterocyclyl each of which may        be substituted by 0, 1 or 2 substituents R⁵⁻¹, the substituents        R⁵⁻¹ being selected independently of one another from the group        consisting of halogen, nitro, amino, trifluoromethyl, hydroxyl,        alkyl and alkoxy,-   R⁶ is alkyl, cycloalkyl, cycloalkenyl or heterocyclyl,    it being possible for R⁶ to be substituted by 0, 1 or 2 substituents    R⁶⁻¹, the substituents R⁶⁻¹ being selected independently of one    another from the group consisting of halogen, nitro, amino,    trifluoromethyl, hydroxyl, alkyl and alkoxy,-   n is a number 0, 1, 2 or 3,    -   it being possible for the radicals R⁵ to be identical or        different when n is 2 or 3,-   m is a number 0, 1, 2, 3 or 4,-   A is aryl or heteroaryl,    and their salts, their solvates and the solvates of their salts.

Compounds of the invention are the compounds of the formula (I) andtheir salts, solvates and solvates of the salts, the compounds of theformula (Ia), mentioned below, that are embraced by formula (I), andtheir salts, solvates and solvates of the salts, and also the compoundsembraced by formula (D) and (Ia) and referred to below as implementationexample(s), and their salts, solvates and solvates of the salts, wherethe compounds referred to below and embraced by formula (I) and/or (Ia)are not already salts, solvates and solvates of the salts.

Depending on their structure the compounds of the invention may exist instereoisomeric forms (enantiomers, diastereomers). The inventiontherefore relates to the enantiomers or diastereomers and theirrespective mixtures. From such mixtures of enantiomers and/ordiastereomers it is possible to isolate the stereoisomerically uniformconstituents in a known way.

The invention relates also, depending on the structure of the compounds,to tautomers of the compounds.

Salts preferred in the context of the invention are physiologicallyacceptable salts of the compounds of the invention.

Physiologically acceptable salts of the compounds (I) embrace acidaddition salts of mineral acids, carboxylic acids and sulfonic acids,e.g., salts of hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid,acetic acid, propionic acid, lactic acid, tartaric acid, malic acid,citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds (I) also embrace saltsof customary bases, such as, by way of example and preferably, alkalimetal salts (e.g., sodium and potassium salts), alkaline earth metalsalts (e.g. calcium and magnesium salts) and ammonium salts derived fromammonia or organic amines having 1 to 16 carbon atoms, such as, by wayof example and preferably, ethylamine, diethylamine, triethylamine,ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclo-hexylamine, dimethylaminoethanol, procaine,dibenzylamine, n-methylmorpholine, dihydroabietylamine, arginine,lysine, ethylenediamine and methylpiperidin.

Solvates in the context of the invention are those forms of thecompounds which in the solid or liquid state form a complex bycoordination with solvent molecules. Hydrates are one specific form ofthe solvates, in which the coordination is with water.

In the context of the present invention the signification of thesubstituents, unless specified otherwise, is as follows

Alkyl per se and “alk” and “alkyl” in alkoxy, alkylamino,alkylaminocarbonyl, alkylcarbonylamino and alkoxycarbonyl are a linearor branched alkyl radical having generally 1 to 8, preferably 1 to 6,more preferably 1 to 4, very preferably 1 to 3 carbon atoms, by way ofexample and preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl,n-pentyl and n-hexyl.

Alkoxy is by way of example and preferably methoxy, ethoxy, n-propoxy,isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylamino is an alkylamino radical having one or two alkyl substituents(chosen independently of one another), the alkyl substituentsindependently of one another having generally 1 to 6, preferably 1 to 4,more preferably 1 to 3 carbon atoms, by way of example and preferablymethylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino,n-pentylamino, n-hexylamino, N,N-dimethylamino, N,N-diethylamino,N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-isopropyl-N-n-propylamino, N-t-butyl-N-methylamino,N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino. Thus C₁-C₃alkylamino is for example a monoalkylamino radical having 1 to 3 carbonatoms or a dialkylamino radical having 1 to 3 carbon atoms in each alkylsubstituent.

Alkylaminocarbonyl is an alkylaminocarbonyl radical having one or twoalkyl substituents (chosen independently of one another), the alkylsubstituents independently of one another having generally 1 to 6,preferably 1 to 4, more preferably 1 to 3 carbon atoms, by way ofexample and preferably methylaminocarbonyl, ethylaminocarbonyl,n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl,n-pentylaminocarbonyl, n-hexylaminocarbonyl, N,N-dimethylaminocarbonyl,N,N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl,N-methyl-N-n-propylaminocarbonyl, N-isopropyl-N-n-propylaminocarbonyl,N-t-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylaminocarbonyl andN-n-hexyl-N-methylaminocarbonyl. C₁-C₃ alkylaminocarbonyl is for examplea monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or adialkylaminocarbonyl radical having 1 to 3 carbon atoms in each alkylsubstituent.

Alkylcarbonylamino is by way of example and preferablymethylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino,isopropylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylaminoand n-hexylcarbonylamino.

Alkoxycarbonyl is by way of example and preferably methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Cycloalkyl is a cycloalkyl group having generally 3 to 8, preferably 5to 7 carbon atoms; specified by way of example and preferably forcycloalkyl are cyclopropyl,

cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In the case of acycloalkyl formed by two aryl substituents together with the aryl carbonatoms to which they are attached, two carbon atoms of the cycloalkylgroup are sp² hybridized.

Cycloalkenyl is a cycloalkyl group having generally 3 to 8, preferably 5to 7 carbon atoms; specified by way of example and preferably forcycloalkenyl are cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl and cycloheptenyl.

Aryl is a mono- to tricyclic aromatic radical having generally 6 to 14carbon atoms; specified by way of example and preferably for aryl arephenyl, naphthyl and phenanthrenyl.

Aryloxy is a mono- to tricyclic aromatic radical, attached via an oxygenatom, and having generally 6 to 14 carbon atoms, by way of example andpreferably phenoxy, naphthyloxy and phenanthrenyloxy.

Arylcarbonylamino is by way of example and preferablyphenylcarbonylamino, naphthylcarbonylamino andphenanthrenylcarbonylamino.

Heteroaryl is an aromatic, mono- or bicyclic radical having generally 5to 10, preferably 5 to 6 ring atoms and up to 5, preferably up to 4,heteroatoms from the series S, O and N; by way of example and preferablythienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl,imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl,indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl.

Heterocyclyl is a mono- or polycyclic, preferably mono- or bicyclic,heterocyclic radical having generally 4 to 10, preferably 5 to 8 ringatoms and up to 3, preferably up to 2, heteroatoms and/or hetero-groupsfrom the series N, O, S, SO, SO₂. The heterocyclyl radicals may besaturated or partly unsaturated. Preference is given to 5- to8-membered, monocyclic saturated heterocyclyl radicals having up to twoheteroatoms from the series O, N and S, such as, by way of example andpreferably, tetrahydrofuran-2-yl, tetrahydrothienyl, pyrrolidin-2-yl,pyrrolidin-3-yl, pyrrolinyl, pyranyl, piperidin-1-yl, piperidin-2-yl,piperidin-3-yl, piperidin-4-yl, thiopyranyl, morpholin-1-yl,morpholin-2-yl, morpholin-3-yl, perhydroazepinyl, piperazin-1-yl,piperazin-2-yl.

Halogen is fluorine, chlorine, bromine and iodine, preferably fluorineand chlorine.

If radicals in the compounds of the invention are substituted, theradicals, unless specified otherwise, may be substituted by one or moreidentical or different substituents. Substitution by up to threeidentical or different substituents is preferred. Very particularpreference is given to substitution by one substituent.

Preference is given in the context of the present invention to compoundsof the formula

in which R¹ to R⁶, A, m and n are as defined for formula (I), and theirsalts, their solvates and the solvates of their salts.

Preference is given in the context of the present invention to compoundsof the invention in which

-   R¹ is 5-, 6-, 9- or 10-membered heteroaryl,    -   where R¹ can be substituted by 0, 1 or 2 substituents R¹⁻¹, the        substituents R¹⁻¹ being selected independently of one another        from the group consisting of halogen, alkyl, amino, alkylamino,        cyano, trifluoromethyl, aryl, heteroaryl, alkoxy, alkoxycarbonyl        and aminocarbonyl,        or-   R¹ is phenyl or naphthyl,    -   where phenyl or naphthyl are substituted by 1, 2 or 3        substituents R¹⁻², the substituents R¹⁻² being selected        independently of one another from the group consisting of        halogen, alkyl, nitro, amino; alkylamino, cyano,        trifluoromethyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,        alkoxy, aryloxy, benzyloxy, alkoxycarbonyl, aminocarbonyl,        alkylcarbonylamino, arylcarbonylamino, alkylaminocarbonyl and        aminosulfonyl,    -   or    -   two substituents R¹⁻², together with the carbon atoms to which        they are attached, form a 5- or 6-membered cycloalkyl or a 5- or        6-membered heterocyclyl,-   R² is hydrogen,-   R³ is hydrogen, hydroxyl, amino, methyl, benzyl, C₁-C₃ alkoxy,    benzyloxy or C₁-C₃ alkylamino,-   R⁴ is methyl,-   R⁵ is fluoro, chloro, trifluoromethyl, trifluoromethoxy, nitro,    amino, alkylamino, hydroxyl, alkoxy, aminocarbonyl, alkoxycarbonyl,    alkyl, phenyl or 5- or 6-membered heteroaryl,    -   or    -   two substituents R⁵, together with the carbon atoms to which        they are attached, form a 5- or 6-membered cycloalkyl or 5- or        6-membered heterocyclyl,-   R⁶ is C₂-C₇ alkyl or 3- to 7-membered cycloalkyl,    -   where R⁶ can be substituted by 0, 1 or 2 substituents R⁶⁻¹, the        substituents R⁶⁻¹ being selected independently of one another        from the group consisting of halogen, alkoxy, alkyl and        trifluoromethyl,-   n is a number 0, 1 or 2,    -   where, if n is 2, the radicals R⁵ can be identical or different,-   m is a number 0, 1, 2 or 3,    and-   A is phenyl, naphthyl or 5-, 6-, 9- or 10-membered heteroaryl.

Preference in the context of the present invention is also given tocompounds of the invention in which

-   R¹ is pyridyl, imidazolyl, thienyl, furyl, oxadiazolyl, pyrazolyl,    pyrazinyl, pyridazinyl, pyrimidinyl, quinolinyl or isoquinolinyl,    -   where R¹ can be substituted by 0, 1 or 2 substituents R¹⁻¹, the        substituents R¹⁻¹ being selected independently of one another        from the group consisting of halogen, alkyl, amino,        trifluoromethyl, phenyl and alkoxy,        or-   R¹ is phenyl or naphthyl,    -   where phenyl or naphthyl are substituted by 1, 2 or 3        substituents R¹⁻², the substituents R¹⁻² being selected        independently of one another from the group consisting of        halogen, C₁-C₄ alkyl, dimethylamino, cyano, trifluoromethyl, 3-        to 7-membered cycloalkyl, 5- or 6-membered heterocyclyl, phenyl,        5- or 6-membered heteroaryl, C₁-C₃ alkoxy, phenyloxy, benzyloxy,        phenylcarbonylamino and aminosulfonyl,    -   or    -   two substituents R¹⁻², together with the carbon atoms to which        they are attached, form a 1,3-benzodioxole or a        1,4-benzodioxane,-   R² is hydrogen,-   R³ is hydrogen, amino, methyl, methoxy, ethoxy, methylamino or    dimethylamino,-   R⁴ is methyl,-   R⁵ is fluoro, chloro, trifluoromethyl, C₁-C₄ alkoxy,    methoxycarbonyl, C₁-C₄ alkyl, phenyl or pyridyl,    -   or    -   two substituents R⁵, together with the phenyl ring to which they        are attached, form a 1,3-benzodioxole or a 1,4-benzodioxane,-   R⁶ is C₃-C₆ alkyl or 3- to 6-membered cycloalkyl,-   n is a number 0, 1 or 2,    -   and, if n is 2, the radicals R⁵ can be identical or different,-   m is a number 0, 1, 2 or 3,    and-   A is phenyl, naphthyl, pyridyl, thienyl, furanyl, quinolinyl or    isoquinolinyl.

Preference in the context of the present invention is also given tocompounds of the invention in which

-   R¹ is pyridyl, thienyl, furyl, quinolinyl or isoquinolinyl,    -   where R¹ can be substituted by 0, 1 or 2 substituents R¹⁻¹, the        substituents R¹⁻¹ being selected independently of one another        from the group consisting of halogen, C₁-C₄ alkyl,        trifluoromethyl, phenyl and C₁-C₃-alkoxy,        or-   R¹ is phenyl or naphthyl,    -   where phenyl or naphthyl are substituted by 1, 2 or 3        substituents R¹⁻², the substituents R¹⁻² being selected        independently of one another from the group consisting of        halogen, C₁-C₄ alkyl, dimethylamino, cyano, trifluoromethyl, 5-        or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, C₁-C₃        alkoxy, phenyloxy or benzyloxy,    -   or    -   two substituents R¹⁻², together with the carbon atoms to which        they are attached, form a 1,3-benzodioxole or a        1,4-benzodioxane,-   R² is hydrogen,-   R³ is hydrogen, amino, methylamino or dimethylamino,-   R⁴ is methyl,-   R⁵ is fluoro, chloro, trifluoromethyl, C₁-C₃ alkoxy, C₁-C₄ alkyl,    phenyl or pyridyl,-   R⁶ is isopropyl, tert-butyl, isopentyl, cyclopentyl or cyclohexyl,-   n is a number 0, 1 or 2,    -   and, if n is 2, the radicals R⁵ can be identical or different,-   m is a number 0, 1 or 2,    and-   A is phenyl, naphthyl, pyridyl, thienyl, quinolinyl or    isoquinolinyl.

Preference in the context of the present invention is also given tocompounds of the invention in which

-   R¹ is pyridyl, thienyl, furyl, quinolinyl or isoquinolinyl,    -   where R¹ can be substituted by 0, 1 or 2 substituents R¹⁻¹, the        substituents R¹⁻¹ being selected independently of one another        from the group consisting of fluoro, chloro, trifluoromethyl,        C₁-C₄ alkyl, phenyl and methoxy.

Preference in the context of the present invention is also given tocompounds of the invention in which

-   R¹ is phenyl or naphthyl,    -   where phenyl or naphthyl are substituted by 1, 2 or 3        substituents R¹⁻², the substituents R¹⁻² being selected        independently of one another from the group consisting of        halogen, C₁-C₄ alkyl, dimethylamino, cyano, trifluoromethyl, 5-        or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, C₁-C₃        alkoxy, phenyloxy or benzyloxy,    -   or    -   two substituents R¹⁻², together with the carbon atoms to which        they are attached, form a 1,3-benzodioxole or a        1,4-benzodioxane.

Preference in the context of the present invention is also given tocompounds of the invention in which R² is hydrogen.

Preference in the context of the present invention is also given tocompounds of the invention in which R³ is hydrogen or amino.

Preference in the context of the present invention is also given tocompounds of the invention in which R⁴ is methyl.

Preference in the context of the present invention is also given tocompounds of the invention in which n is the number zero.

Preference in the context of the present invention is also given tocompounds of the invention in which n is the number 1, A is phenyl andR⁵ is fluoro, chloro, trifluoromethyl, alkoxy, C₁-C₄ alkyl, phenyl orpyridyl, R⁵ being positioned meta or para to the linkage site of thephenyl ring. By the linkage site of the phenyl ring is meant the carbonatom of the phenyl ring carrying R⁵ to which the phenyl ring carryingR⁵, in accordance with formula (I) or (Ia) as A, is attached to theremainder of the compound.

Preference in the context of the present invention is also given tocompounds of the invention in which R⁶ is C₃-C₆ alkyl or 3- to6-membered cycloalkyl, especially isopropyl, isobutyl, 1-methylpropyl orcyclopentyl, very particularly isopropyl or cyclopentyl.

Preference in the context of the present invention is also given tocompounds of the invention in which m is the number zero.

Preference in the context of the present invention is also given tocompounds of the invention in which A is phenyl, naphthyl, pyridyl,thienyl, quinolinyl or isoquinolinyl.

Preference in the context of the present invention is also given tocompounds of the invention in which A is phenyl.

Preference in the context of the present invention is also given to thefollowing compounds:

-   6-fluoro-N-{(1S)-3-[((1S)-2-methyl-1-{[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]-carbonyl}propyl)amino]-3-oxo-1-phenylpropyl}-2-pyridinecarboxamide-   N-{(1S)-3-[((1S)-2-methyl-1-{[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]carbonyl}-propyl)amino]-3-oxo-1-phenylpropyl}-3-quinolinecarboxamide-   N-{(1S)-3-[((1S)-2-methyl-1-{[(3R,4S)₄-methyl-2,5-dioxo-3-pyrrolidinyl]-carbonyl}propyl)amino]-3-oxo-1-phenylpropyl}4-phenyl-2-pyridinecarboxamide-   N-[(1S)-3-({(1S)-1-cyclohexyl-2-[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]-2-oxoethyl}amino)-3-oxo-1-phenylpropyl]-6-fluoro-2-pyridinecarboxamide-   N-[(1S)-3-({1-cyclopentyl-2-[(3R,4S)₄-methyl-2,5-dioxo-3-pyrrolidinyl]-2-oxoethyl}amino)-3-oxo-1-phenylpropyl]-2-pyridinecarboxamide-   (3S)-N-((1S)-2-methyl--{[(3R,4S)₄-methyl-2,5-dioxo-3-pyrrolidinyl]-carbonyl}propyl)-3-phenyl-3-[(2-thienylacetyl)amino]propanamide-   N-[(1S)-3-({(1S)-1-cyclopentyl-2-[(3R,4)₄-methyl-2,5-dioxo-3-pyrrolidinyl]-2-oxoethyl}amino)-3-oxo-1-phenylpropyl]-4-phenyl-2-pyridinecarboxamide-   N-[(1S)-3-({(1S)-1-cyclopentyl-2-[(3R,4)-4-methyl-2,5-dioxo-3-pyrrolidinyl]-2-oxoethyl}amino)-3-oxo-1-phenylpropyl]-3-quinolinecarboxamide-   N-[(1S)-3-({(1S)-1-cyclopentyl-2-[(3R,4S)₄-methyl-2,5-dioxo-3-pyrrolidinyl]-2-oxoethyl}amino)-3-oxo-1-phenylpropyl]-5-fluoro-1H-indole-2-carboxamide

The invention further provides a process for preparing compounds of theformula (I), where

-   [A] compounds of the formula    in which R² to R⁶, A and n are as defined above, are reacted with    compounds of the formula    in which R¹ and m are as defined above,    it being possible for these to be in activated form if desired,    or-   [B] compounds of the formula    in which R³, R⁴ and R⁶ are as defined above,    are reacted with compounds of the formula    in which R¹, R², R⁵, A, m and n are as defined above,    it being possible for these to be in activated form if desired.

Suitable for converting the compounds into the activated form in theabovementioned processes are, for example, carbodiimides such asN,N′-diethyl-, N,N,′-dipropyl-, N,N′-diisopropyl-,N,N′-dicyclohexylcarbodiimide,N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)(optionally in the presence of pentafluorophenol (PFP)),N-cyclohexylcarbodiimide-N′-propyloxymethyl-polystyrene(PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfateor 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compoundssuch as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic anhydride, or isobutyl chloroformate, orbis(2-oxo-3-oxazolidinyl)phosphoryl chloride orbenzotriazolyloxytri(dimethylamino)phosphonium hexafluorophosphate, orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), orbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), or mixtures of these with bases.

Bases are, for example, alkali metal carbonates, such as sodium orpotassium carbonate, or hydrogencarbonate, or organic bases such astrialkylamines, e.g. triethylamine, N-methylmorpholine,N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

Preference is given to using HATU with diisopropylethylamine and usingEDC with HOBt and triethylamine.

Suitable solvents in this context include inert organic solvents whichdo not change under the reaction conditions. These include halogenatedhydrocarbons such as dichloromethane or trichloromethane, hydrocarbonsuch as benzene, xylene, toluene, hexane, cyclohexane, or petroleumfractions, nitromethane, dimethylformamide or acetonitrile or etherssuch as diethyl ether, tetrahydrofuran or dioxane. It is also possibleto use mixtures of the solvents. Particular preference is given todichloromethane or a mixture of dichloromethane and dimethylformamide.

Process [A]

The compounds of the formula (II) are known or can be prepared byadmixing compounds of the formula

in which R² to R⁶, A and n are as defined above,with acid, in particular with hydrochloric acid or trifluoroacetic acid.The compounds of the formula (II) are in this case obtained in the formof the corresponding salts, e.g., in the form of their hydrochlorides,and can be used further in this form or converted by chromatographicpurification into their salt-free form.

Suitable solvents in this context include inert organic solvents whichdo not change under the reaction conditions. These include halogenatedhydrocarbons such as dichloromethane or trichloromethane, hydrocarbonssuch as benzene, xylene, toluene, hexane, cyclohexane, or petroleumfractions, nitromethane, dimethylformamide or acetonitrile or etherssuch as diethyl ether, tetrahydrofuran or dioxane. It is also possibleto use mixtures of the solvents. Particular preference is given to theuse of hydrochloric acid in dioxane or trifluoroacetic acid indichloromethane.

The compounds of the formula (VI) are known or can be prepared byreacting compounds of the formula (IV) with compounds of the formula

in which R², R⁵, A and n are as defined above,it being possible for these to be in activated form if desired.

Suitable for converting the compounds into the activated form are, forexample, carbodiimides such as N,N′-diethyl-, N,N,′-dipropyl-,N,N′-diisopropyl-, N,N′-dicyclohexylcarbodiimide,N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)(optionally in the presence of pentafluorophenol (PFP)),N-cyclohexylcarbodiimide-N′-propyloxymethyl-polystyrene(PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfateor 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compoundssuch as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic anhydride, or isobutyl chloroformate, orbis(2-oxo-3-oxazolidinyl)phosphoryl chloride orbenzotriazolyloxytri(dimethylamino)phosphonium hexafluorophosphate, orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), orbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), or mixtures of these with bases.

Bases are, for example, alkali metal carbonates, such as sodium orpotassium carbonate, or hydrogencarbonate, or organic bases such astrialkylamines, e.g. triethylamine, N-methylmorpholine,N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

Preference is given to using HATU and diisopropylethylamine or EDC withHOBt and triethylamine.

Suitable solvents in this context include inert organic solvents whichdo not change under the reaction conditions. These include halogenatedhydrocarbons such as dichloromethane or trichloromethane, hydrocarbonsuch as benzene, xylene, toluene, hexane, cyclohexane, or petroleumfractions, nitromethane, dimethylformamide or acetonitrile or etherssuch as diethyl ether, tetrahydrofuran or dioxane. It is also possibleto use mixtures of the solvents. Particular preference is given to amixture of dichloromethane and dimethylformamide.

The compounds of the formula (IV) are known from the literature or newand can be prepared by admixing compounds of the formula

in which R³, R⁴ and R⁶ are as defined above,with acid, in particular with hydrochloric acid or trifluoroacetic acid.

Suitable solvents in this context include inert organic solvents whichdo not change under the reaction conditions. These include halogenatedhydrocarbons such as dichloromethane or trichloromethane, hydrocarbonssuch as benzene, xylene, toluene, hexane, cyclohexane, or petroleumfractions, nitromethane, dimethylformamide or acetonitrile or etherssuch as diethyl ether, tetrahydrofuran or dioxane. It is also possibleto use mixtures of the solvents. Particular preference is given to theuse of hydrochloric acid in dioxane or trifluoroacetic acid indichloromethane.

The compounds of the formula (VII) are known or can be prepared byprocedures known from the literature. (With regard to the preparation ofaromatic beta-amino acids see for example: S. Rault, P. Dallemagne, M.Robba, Bull. Soc. Chim. Fr., 1987, 1079-1083; S. G. Davies et al., J.Chem. Soc., Chem. Commun. 1993, 1153-1155; V. A. Soloshonok et al.,Tetrahedron Asymmetry, 1995, 1601-1610; regarding the reaction to formthe tert-butoxycarbonyl-protected compounds see T. W. Greene, P. G. M.Wuts, Protective Groups in Organic Synthesis, 3d Edt. 1999, J. Wiley &Sons, Inc.).

The compounds of the formula (VIII) are known or can be prepared bymethods known from the literature. (Cf., e.g., S. G. Davies, D. J.Dixon, J. Chem. Soc., Perkin Trans. 1, 1998, 17, 2635-2643; A. V. RamaRao, A. K. Singh, Ch. V. N. S. Varaprasad, Tetrahedron Letters, 1991,32, 4393-4396).

The compounds of the formula (III) are known or can be prepared bymethods known from the literature (Houben-Weyl, Methoden der organischenChemie, vol. E5, Carboxylic acids and carboxylic acid derivatives,Thieme Verlag, Stuttgart, 1985).

Process [B]

The compounds of the formula (V) are known from the literature or newand can be prepared by hydrolyzing compounds of the formula

in which R¹, R², R⁵, A, m and n are as defined above and R⁷ is an alkylradical.

The hydrolysis can be carried out in accordance with standard methods,e.g., in a mixture of ethanol and water with 40% strength sodiumhydroxide solution at room temperature or in a mixture of dioxane andwater with 10% strength methanolic potassium hydroxide solution.

The compounds of the formula (IX) are known from the literature or newand can be prepared by reacting compounds of the formula

in which R², R⁵, R⁷, A and n are as defined above,with compounds of the formula (III), it being possible for these to bein activated form if desired.

Suitable for converting the compounds into the activated form in theabovementioned processes are, for example, carbodiimides such asN,N′-diethyl-, N,N,′-dipropyl-, N,N′-diisopropyl-,N,N′-dicyclohexylcarbodiimide,N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)(optionally in the presence of pentafluorophenol (PFP)),N-cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene (PS-carbodiimide)or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazoliumcompounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfate or2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compoundssuch as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic anhydride, or isobutyl chloroformate, orbis(2-oxo-3-oxazolidinyl)phosphoryl chloride orbenzotriazolyloxytri(dimethylamino)phosphonium hexafluorophosphate, orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), orbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), or mixtures of these with bases.

Bases are, for example, alkali metal carbonates, such as sodium orpotassium carbonate, or hydrogencarbonate, or organic bases such astrialkylamines, e.g., triethylamine, N-methylmorpholine,N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

Preference is given to using HATU with diisopropylethylamine and usingEDC with HOBt and triethylamine.

Suitable solvents in this context include inert organic solvents whichdo not change under the reaction conditions. These include halogenatedhydrocarbons such as dichloromethane or trichloromethane, hydrocarbonsuch as benzene, xylene, toluene, hexane, cyclohexane, or petroleumfractions, nitromethane, dimethylformamide or acetonitrile or etherssuch as diethyl ether, tetrahydrofuran or dioxane. It is also possibleto use mixtures of the solvents. Particular preference is given todichloromethane or a mixture of dichloromethane and dimethylformamide.

The compounds of the formula (X) are known from the literature or newand can be prepared in analogy to methods known from the literature(With regard to the preparation of aromatic beta-amino acids and theirconversion into the corresponding alkyl esters see for example: S.Rault, P. Dallemagne, M. Robba, Bull. Soc. Chim. Fr., 1987, 1079-1083;S. G. Davies et al., J. Chem. Soc., Chem. Commun. 1993, 1153-1155; V. A.Soloshonok et al., Tetrahedron Asymmetry, 1995, 1601-1610; S. J.Faulconbridge et al., Tetrahedron Letters, 2000, 41, 2679-2682).

Synthesis may also take place on a polymeric support. In that case R² inthe synthesis sequence is a polymer (resin), preference being given tothe use of 4-(4-formyl-3-methoxyphenoxy)butyryl-aminomethyl-polystyreneor another resin in which a polymeric backbone such as polystyrene orblock copolymers of polystyrene with ethylene glycol has attached to itvia a linker group such as 3-methoxyphenoxyethyl,3,5-dimethoxyphenoxyethoxymethyl or 3-methoxyphenoxybutyrylaminomethyl aformyl radical or another radical which allows amines to be attached tothe polymeric support.

The preparation of the compounds of the invention can be illustrated bythe following synthesis schemes:Starting Compounds:

Preparation Examples:

Solid Phase Synthesis:

The present invention further provides compounds of the formula (1) forcontrolling diseases, particularly bacterial diseases, and alsomedicinal products comprising compounds of the formula (1) andauxiliaries, and also for the use of compounds of the formula (I) forproducing a medicinal product for treating bacterial diseases.

The formulations of the invention are particularly active againstbacteria and bacterialike microorganisms. They are thereforeparticularly suitable for the prophylaxis and chemotherapy of local andsystemic infections in human and veterinary medicine that are induced bythese pathogens.

By way of example it is possible to treat and/or prevent local and/orsystemic diseases caused by the following pathogens or by combinationsof the following pathogens:

Gram-positive cocci, e.g., staphylococci (Staph. aureus, Staph.epidermidis), enterococci (E. faecalis, E. faecius) and streptococci(Strept. agalactiae, Strept. pneumoniae); gram-negative cocci (Neisseriagonorrhoeae) and gram-negative rods such as enterobacteria, e.g.,Escherichia coli, Haemophilus influenzae, citrobacter (Citrob. freundii,Citrob. divernis), salmonella and shigella; and also klebsiellas (Klebs.pneumoniae, Klebs. oxytocy), enterobacter (Ent. aerogenes, Ent.agglomerans), hafnia, serratia (Serr. marcescens), providencia,yersinia, and also the genus Acinetobacter. The antibacterial spectrumfurther embraces strictly anaerobic bacteria such as Bacteroidesfragilis, representatives of the genus Peptococcus, Peptostreptococcusand the genus Clostridium; and also mycoplasmas (M. pneumoniae, M.hominis, M. urealyticum) and mycobacteria, e.g., Mycobacteriumtuberculosis.

The above listing of pathogens should be interpreted merely as exemplaryand in no way as restrictive. Examples that may be mentioned of diseaseswhich may be caused by the stated pathogens or combination infectionsand which may be prevented, remedied or cured by the formulations of theinvention include the following:

Infectious diseases in humans, such as septic infections, bone and jointinfections, skin infections, postoperative wound infections, abscesses,phlegmons, wound infections, infected burns, burn wounds, infections inthe oral region, infections following dental operations, septicarthritis, mastitis, tonsillitis, genital infections and eye infections.

As well as in humans, bacterial infections in other species too can betreated. Examples that may be mentioned include the following:

pigs: coli diarrhea, enterotoxemia, sepsis, dysenteria, salmonellosis,metritis-mastitis-agalactia syndrome, mastitis;

ruminants (cattle, sheep, goats): diarrhea, sepsis, bronchopneumonia,salmonellosis, pasteurellosis, mycoplasmosis, genital infections;

horses: bronchopneumonias, joint ill, puerperal and postpartuminfections, salmonellosis;

dogs and cats: bronchopneumonia, diarrhea, dermatitis, otitis, urinarytract infections, prostatitis;

poultry (chickens, turkeys, quails, pigeons, ornamental birds andothers): mycoplasmosis, E. coli infections, chronic respiratory tractdiseases, salmonellosis, pasteurellosis, psittacosis.

It is also possible to treat bacterial diseases associated with thebreeding and keeping of farmed and ornamental fish, in which case theantibacterial spectrum extends beyond the aforementioned pathogens toembrace further pathogens such as Pasteurella, Brucella, Campylobacter,Listeria, Erysipelothris, Corynebacteria, Borellia, Treponema, Nocardia,Rickettsi, Yersinia, for example.

The active ingredient may act systemically and/or locally. For thatpurpose it can be administered in appropriate manner, such as orally,parenterally, pulmonically, nasally, sublingually, lingually, buccally,rectally, transdermally, conjunctivally, otically or as an implant.

For these administration routes the active ingredient can beadministered in suitable administration forms.

Administration forms suitable for oral administration are known suchforms which deliver the active ingredient rapidly and/or in a modifiedway, such as tablets (uncoated and coated tablets, such as film-coatedtablets or tablets provided with enteric coatings), capsules,sugar-coated tablets, granules, pellets, powders, emulsions, suspensionsand solutions.

Parenteral administration can be made with avoidance of an absorptionstep (intravenously, intraarterially, intracardially, intraspinally orintralumbarly) or with inclusion of absorption (intramuscularly,subcutaneously, intracutaneously, percutaneously, or intraperitoneally).Administration forms suitable for parenteral administration includepreparations for injection and infusion in the form of solutions,suspensions, emulsions, lyophilisates and sterile powders.

Preference is given to parenteral administration, more particularlyintravenous administration.

Examples suitable for the other administration routes are pharmaceuticalforms for inhalation (including powder inhalers, nebulizers), nasaldrops/solutions, sprays; capsules or tablets to be administeredlingually, sublingually or buccally, suppositories, ear and eyepreparations, vaginal capsules, aqueous suspensions (lotions, shakingmixtures), lipophilic suspensions, ointments, creams, milk, pastes,dusting powders or implants.

The active ingredients can be converted in conventional manner into thestated administration forms. This is done with the use of inert,nontoxic, pharmaceutically appropriate auxiliaries (excipients). Theseinclude, among others, carriers (e.g., microcrystalline cellulose),solvents (e.g. liquid polyethylene glycols), emulsifiers (e.g., sodiumdodecyl sulfate), dispersants (e.g., polyvinylpyrrolidone), syntheticand natural biopolymers (e.g., albumen), stabilizers (e.g., antioxidantssuch as ascorbic acid), colorants (e.g., inorganic pigments such as ironoxides) or flavor and/or odor masking agents.

It has generally proven advantageous in the case of parenteraladministration to administer amounts of about 5 to 250 mg/kg body weightper 24 hours in order to achieve effective results. In the case of oraladministration the amount is about 5 to 100 mg/kg body weight per 24hours.

It may nevertheless be necessary, where appropriate, to deviate from theamounts specified, specifically as a function of body weight,administration route, individual response to the active ingredient, typeof formulation, and time or interval at which administration takesplace.

The percentages in the tests and examples below, unless statedotherwise, are percentages by weight; parts are parts by weight. Solventratios, dilution ratios and concentration figures for liquid/liquidsolutions are based in each case on the volume.

A. EXAMPLES

Reaction schemes which are shown for general procedures show a selectionof examples, but can be employed in each case for all of the exampleswhich refer to them.

A. Abbreviations:

-   Boc tert-butoxycarbonyl-   CDCl₃ deuterochloroform-   DCI direct chemical ionization-   DIEA N,N-diisopropylethylamine-   DMSO dimethyl sulfoxide-   EDC N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride-   eq. equivalent-   ES electrospray ionization (for MS)-   Fmoc fluorenylmethoxycarbonyl-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   h hour-   HOBt 1-hydroxylbenzotriazole-   HPLC high-pressure, high-performance liquid chromatography-   LC-MS liquid chromatography-coupled mass spectroscopy-   MS mass spectroscopy-   MW molecular weight [g/mol]-   NMR nuclear magnetic resonance spectroscopy-   PS-DIEA N,N-diisopropylethylamine-polystyrene (Resin)-   R_(f) retention index (for TLC)-   RP-HPLC reverse phase HPLC-   RT room temperature-   R_(t) retention time (for HPLC)-   THF tetrahydrofuran    HPLC and LC-MS Methods:

Method 1: column: Kromasil C18, L-R temperature: 30° C., flow rate=0.75ml min⁻¹, mobile phase: A=0.01 M HClO₄, B=acetonitrile, gradient: →0.5min 98% A→4.5 min 10% A→6.5 min 10% A.

Method 2: column: Kromasil C18 60*2 mm, L-R temperature: 30° C., flowrate=0.75 ml min⁻¹, mobile phase: A=0.01 M H₃PO₄, B=acetonitrile,gradient: →0.5 min 90% A→4.5 min 10% A→6.5 min 10% A.

Method 3: column: Kromasil C18 60*2 mm, L-R temperature: 30° C., flowrate=0.75 ml min⁻¹, mobile phase: A=0.005 M HClO₄, B=acetonitrile,gradient: →0.5 min 98% A→4.5 min 10% A→6.5 min 10% A.

Method 4: column: Symmetry C18 2.1×150 mm, column oven: 50° C., flowrate=0.6 ml min⁻¹, mobile phase: A=0.6 g 30% strength hydrochloricacid/1 water, B=acetonitrile, gradient: 0.0 min 90% A→4.0 min 10% A→9min 10% A.

Method 5: Instrument: Micromass Quattro LCZ

Column: Symmetry C18, 50 mm×2.1 mm, 3.5 μm, temperature: 40° C., flowrate=0.5 ml min⁻¹, mobile phase A=acetonitrile+0.1% formic acid, mobilephase B=water+0.1% formic acid, gradient: 0.0 min 10% A→4 min 90% A→6min 90% A.

Method 6: Instrument: Micromass Platform LCZ

Column: Symmetry C18, 50 mm×2.1 mm, 3.5 μm, temperature: 40° C., flowrate=0.5 ml min⁻¹, mobile phase A=acetonitrile+0.1% formic acid, mobilephase B=water+0.1% formic acid, gradient: 0.0 min 10% A o 4 min 90% A→6min 90% A.

Method 7: Instrument: Micromass Quattro LCZ

Column: Symmetry C18, 50 mm×2.1 mm, 3.5 μm, temperature: 40° C., flowrate=0.5 ml min⁻¹, mobile phase A=acetonitrile+0.1% formic acid, mobilephase B water+0.1% formic acid, gradient: 0.0 min 5% A→1 min 5% A o 5min 90% A→6 min 90% A.

Method 8: column: Symmetry C18 2.1×150 mm, 5 μm, column oven: 70° C.,flow rate=0.9 ml min⁻¹, mobile phase: A=acetonitrile, B=0.3 g 30%strength hydrochloric acid/1 water, gradient: 0.0 min 2% A→2.5 min 95%A→5 min 95% A.

Method 9: column: Symmetry C18 3.9×150 mm, column oven: 40° C., flowrate=1.5 ml min⁻¹, mobile phase: A=water+0.05% H₃PO₄, B=acetonitrile,gradient: 0.0 min 10% B→0.6 min 10% B→3.8 min 100% B→5.0 min 100% B.

Method 10: Instrument: Waters Alliance 2790 LC; column: Symmetry C18, 50mm×2.1 mm, 3.5 μm; mobile phase A: water+0.1% formic acid, mobile phaseB: acetonitrile+0.1% formic acid; gradient: 0.0 min 5% B→5.0 min 10%B→6.0 min 10% B; temperature: 50° C., flow rate: 1.0 m/min, UVdetection: 210 nm.

Method 11: Instrument type MS: Micromass ZQ; instrument type HPLC:Waters Alliance 2790; column: Symmetry C 18, 50 mm×2.1 mm, 3.5 μm;mobile phase B: acetonitrile+0.05% formic acid, mobile phase A:water+0.05% formic acid; gradient: 0.0 min 10% B→3.5 min 90% B→5.5 min90% B; oven: 50° C., flow rate: 0.8 ml/min, UV detection: 210 nm.

Method 12: Instrument: Waters Alliance 2790 LC; column: Symmetry C18, 50mm×2.1 mm, 3.5 μm; mobile phase A: water+0.05% formic acid, mobile phaseB: acetonitrile+0.05% formic acid; gradient: 0.0 min 5% B→4.5 min 10%B→5.5 min 10% B; temperature: 50° C., flow rate: 1.0 ml/min, UVdetection: 210 nm.

Method 13: Instrument: Micromass Quattro LCZ, HP1100; column: SymmetryC18, 50 mm×2.1 mm, 3.5 μm; mobile phase A: water+0.05% formic acid,mobile phase B: acetonitrile+0.05% formic acid; gradient: 0.0 min 90%A→4.0 min 10% A→6.0 min 10% A; Oven: 40° C., flow rate: 0.5 ml/min, UVdetection: 208-400 nm.

Method 14: Instrument: Micromass Platform LCZ, HP1100; column: SymmetryC18, 50 mm×2.1 mm, 3.5 μm; mobile phase A: water+0.05% formic acid,mobile phase B: acetonitrile+0.05% formic acid; gradient: 0.0 min 90%A→4.0 min 10% A→6.0 min 10% A; oven: 40° C., flow rate: 0.5 ml/min, UVdetection: 208-400 nm.

Method 15: Instrument: Waters Alliance 2790 LC; column: Symmetry C18, 50mm×2.1 mm, 3.5 μm; mobile phase A: water+0.05% formic acid, mobile phaseB: acetonitrile+0.05% formic acid; gradient: 0.0 min 10% B→4.0 min 90% Bo 6.0 min 90% B; temperature: 50° C., flow rate: 0.0 min 0.5 ml/min→4.0min 0.8 ml/min, UV detection: 210 nm.

Method 16: Instrument type MS: Micromass ZQ; intrument type HPLC: WatersAlliance 2790; column: Symmetry C 18, 50 mm×2.1 mm, 3.5 μm; mobile phaseB: acetonitrile+0.05% formic acid, mobile phase A: water+0.05% formicacid; gradient: 0.0 min 5% B→4.5 min 90% B→5.5 min 90% B; oven: 50° C.,flow rate: 1.0 ml/, UV detection: 210 nm.

Method 17: Instrument type MS: Micromass ZQ; instrument type HPLC:Waters Alliance 2790; column: Uptisphere C 18, 50 mm×2.0 mm, 3.0 μm;mobile phase B: acetonitrile+0.05% formic acid, mobile phase A:water+0.05% formic acid; gradient: 0.0 min 5% B→2.0 min 40% B→4.5 min90% B→5.5 min 90% B; oven: 45° C., flow rate: 0.0 min 0.75 ml/min→4.5min 0.75 ml/min→5.5 min 1.25 ml/min, UV detection: 210 nm.

Method 18: Instrument: Micromass Platform LCZ with HPLC Agilent series1100; column: Grom-SIL120 ODS-4 HE, 50 mm×2.0 mm, 3 μm; mobile phase A:1 l water+1 ml 50% strength formic acid, mobile phase B: 1 lacetonitrile+1 ml 50% strength formic acid; gradient: 0.0 min 100% A→0.2min 100% A→2.9 min 30% A→3.1 min 10% A→4.5 min 10% A; oven: 55° C., flowrate: 0.8 ml/min, UV detection: 208-400 nm.

Method 19: Instrument: Micromass Quattro LCZ, with HPLC Agilent series1100; column: Grom-SIL120 ODS-4 HE, 50 mm×2.0 mm, 3 μm; mobile phase A:1 l water+1 ml 50% strength formic acid, mobile phase B: 1 lacetonitrile+1 ml 50% strength formic acid; gradient: 0.0 min 100% A→0.2min 100% A→2.9 min 30% A→3.1 min 10% A→4.5 min 10% A; oven: 55° C., flowrate: 0.8 ml/min, UV detection: 208-400 nm.

Method 20: Instrument type MS: Micromass ZQ; instrument type HPLC:Waters Alliance 2790; column: Grom-Sil 120 ODS-4 HE 50×2 mm, 3.0 μm;mobile phase B: acetonitrile+0.05% formic acid, mobile phase A:water+0.05% formic acid; gradient: 0.0 min 5% B→2.0 min 40% B→4.5 min90% B→5.5 min 90% B; oven: 45° C.; flow rate: 0.0 min 0.75 ml/min 4.5min 0.75 ml/min→5.5 min 1.25 ml/min; UV detection: 210 nm.

Method 21: Instrument type MS: Micromass ZQ; instrument type HPLC:Waters Alliance 2790; column: Grom-Sil 120 ODS-4 HE 50×2 mm, 3.0 μm;mobile phase B: acetonitrile+500 ul 50% strength formic acid/1; mobilephase A: water+500 μl 50% strength formic acid/1; gradient: 0.0 min 0%B+0.2 min 0% B→2.9 min 70% B→3.1 min 90% B→4.5 min 90% B, oven: 50° C.,flow rate: 0.8 ml/min; UV detection: 210 nm.

Method 22: Instrument: Micromass Quattro LCZ with HPLC Agilent series1100; column: UPTISPHERE HDO, 50 mm×2.0 mm, 3 μm; mobile phase A: 1 lwater+1 ml 50% strength formic acid, mobile phase B: 1 l acetonitrile+1ml 50% strength formic acid; gradient: 0.0 min 100% A→0.2 min 100% A→2.9min 30% A→3.1 min 10% A→4.5 min 10% A; oven: 55° C., flow rate: 0.8ml/min, UV detection: 208-400 nm.

Starting Compounds:

Example 1A (3S)-1,3-Dimethyl-2,5-pyrrolidinedione

600 mg (5.26 mmol) of (3S)-3-methyldihydro-2,5-furandione (preparation:S. G. Davies, D. J. Dixon, J. Chem. Soc., Perkin Trans. 1, 1998, 17,2635-2643) are introduced to a vessel together with 559 mg (0.77 ml,5.52 mmol) of triethylamine in 5 ml of dichloromethane at 0° C., and 373mg (5.52 mmol) of methylamine hydrochloride are added. The reactionmixture is stirred at room temperature overnight and then 938 mg (5.78mmol) of N,N-carbonyldiimidazole are added in portions. The mixture isstirred at room temperature for 1.5 h and at reflux temperature for 30minutes. After it has cooled to room temperature the reaction mixture iswashed with 5% strength hydrochloric acid and water, the organic phaseis dried over magnesium sulfate, filtered and concentrated and theproduct is dried under a high vacuum. This gives 605 mg of the product(88% of theory).

MS (ES+): m/z (%)=128 (M+H⁺) (100).

HPLC (method 6): R_(t)=0.81 min.

¹H-NMR (300 MHz, CDCl₃): δ=3.10 (dd, 1H), 2.99 (s, 3H), 2.90-2.82 (m,1H), 2.32 (dd, 1H), 1.35 (d, 3H).

Example 2A(3R,4S)-3-[(2S)-2-(tert-Butoxycarbonyl)amino-3-methylbutanoyl]-1,4-dimethyl-2,5-pyrrolidinedione

684 mg (3.15 mmol) of N-(tert-butoxycarbonyl)-L-valine and 561 mg (3.46mmol) of N,N-carbonyldiimidazole are stirred in 4 ml of tetrahydrofuranat room temperature for 2 h. Then 400 mg (3.15 mmol) of(3S)-3-1,3-dimethyl-2,5-pyrrolidinedione are added to this mixture andthe whole mixture is added dropwise over the course of 30 minutes to 6.3ml of a 1 molar solution of lithium hexamethyldisilazide in THF, whichhas been cooled to −65° C. After the end of the addition stirring iscontinued at −65° C. for 15 minutes more, and then 6 ml of saturatedaqueous ammonium chloride are added. After the reaction mixture has beenwarmed to room temperature it is diluted with diethyl ether and theorganic phase is washed with saturated aqueous sodium chloride solutionand subsequently concentrated. The crude product is purified by RP-HPLC(mobile phase: water-acetonitrile, gradient). This gives 223 mg (22% oftheory) of the desired product.

MS (ES−): m/z (%)=325 (M−H⁺) (35).

HPLC (method 5): R_(t)=3.99 min.

¹H-NMR (200 MHz, CDCl₃): δ=5.70 (br. d, 1H), 4.57 (dd, 1H), 3.78 (d,1H), 3.47-3.30 (m, 1H), 2.98 (s, 3H), 2.50-2.32 (m, 1H), 1.46 (s, 9H),1.32 (d, 3H), 1.02 (d, 3H), 0.80 (d, 3H).

In the same way it is possible by reacting the correspondingN-tert-butoxycarbonyl-protected amino acids with(3S)-1-(benzyloxy)-3-methyl-2,5-pyrrolidinedione (preparation: S. G.Davies, D. J. Dixon, J. Chem. Soc., Perkin Trans. 1, 1998, 17,2635-2643) to prepare the following derivatives: Example Structure MW MSHPLC 3A

432.52 MS (ES−), m/z (%): 431 (M − H)⁻ (100) HPLC (method 6): R_(t) =4.87 min 4A

432.51 MS (ES−), m/z (%): 431 (M − H)⁻ (100) HPLC (method 10): R_(t) =4.10 min 5A

458.55 MS (ES−), m/z (%): 457 (M − H)⁻ (100) HPLC (method 12): R_(t) =4.12 min 6A

444.53 MS (ES−), m/z (%): 443 (M − H)⁻ (100) HPLC (method 12): R_(t) =3.97 min

General instructions A: Reductive deprotection of1-benzyloxy-2,5-pyrrolidinediones

Deprotection takes place in a manner similar to that of S. G. Davies, D.J. Dixon, J. Chem. Soc., Perkin Trans. 1, 1998, 17, 2635-2643.

The 1-benzyloxy-2,5-pyrrolidinedione (1 eq.) is dissolved in methanol(about 0.02 mol/l), a catalytic amount of palladium-on-carbon (10%) isadded, and the mixture is stirred under a hydrogen atmosphere(atmospheric pressure) for 1 h. The reaction mixture is then filteredand concentrated. The residue is dissolved in acetonitrile (about 0.05mol/l) and added dropwise at room temperature to a solution of2-bromoacetophenone (1 eq) in acetonitrile (about 0.03 mol/l) at roomtemperature. Thereafter over a period of 2 h, 1.5 eq. of triethylaminein acetonitrile (about 0.35 mol/l) are added dropwise to the reactionmixture. The reaction mixture is stirred at room temperature overnightand concentrated and the crude product is purified by means of RP-HPLC(mobile phase: acetonitrile/water+0.3 ml 37% strength hydrochloricacid/l, gradient).

In accordance with general instructions A it is possible to obtain thefollowing compounds: Example Structure MW MS HPLC 7A

326.40 MS (ES+), m/z (%): 327 (M + H)⁺ (100) HPLC (method 5): R_(t) =3.87 min 8A

326.40 MS (ES+), m/z (%): 349 (M + Na)⁺ (100) HPLC (method 12): R_(t) =2.97 min 9A

352.43 MS (ES−), m/z (%): 351 (M − H)⁻ (100) HPLC (method 12): R_(t) =3.23 min 10A 

338.40 MS (ES−), m/z (%): 337 (M − H)⁻ (100) HPLC (method 13): R_(t) =4.16 min

Example 11A(3R,4S)-3-[(2S)-2-Amino-3-methylbutanoyl]-4-methyl-2,5-pyrrolidinedionehydrochloride

A solution, cooled at 0° C., of 4.40 g (14.09 mmol) of(3R,4S)-3-[(2S)-2-(tert-butoxycarbonyl)amino-3-methylbutanoyl]-4-methyl-2,5-pyrrolidinedione(preparation: S. G. Davies, D. J. Dixon, J. Chem. Soc., Perkin Trans. 1,1998, 17, 2635-2643) in dioxane is admixed dropwise with 35 ml of 4Nhydrochloric acid solution in 1,4-dioxane. When the addition is at anend the mixture is warmed to room temperature and stirred for 2 h, afterwhich the mixture is concentrated under reduced pressure. The crudeproduct can be used directly in the next stage. If desired the residueis treated with diethyl ether and the crystals precipitated are filteredoff and dried under a high vacuum.

Yield: 2.99 g (86% of theory).

MS (ES+): m/z (%)=213 (M+H⁺) (100).

HPLC (method 4): R_(t)=0.41 min.

In the same way it is possible, from the correspondingtert-butoxycarbonylamino derivatives, by treatment with hydrochloricacid in dioxane, to prepare the following amines in the form of theirhydrochlorides and to react them further directly: Example Structure MWMS 12A

226.28 MS (ES+), m/z (%): 227 (M + H)⁺ (80) 13A

226.28 MS (ES+), m/z (%): 227 (M + H)⁺ (100) 14A

226.28 15A

252.32 16A

238.29

General instructions B: Preparation of the beta-amino acid methyl esters

The beta-amino [synthesis according to instructions known from theliterature (e.g., S. Rault P. Dallemagne, M. Robba, Bull. Soc. Chim.Fr., 1987, 1079-1083; L. Lázár, T. Martinek, G. Bernáth, F. Fülöp,Synth. Comm., 1998, 28, 219-224)] is 0.5 to 1.0 moil) and admixeddropwise at 0° C. with 1.2 eq. of thionyl chloride. After the end of theaddition the reaction mixture is stirred at room temperature overnightand then concentrated. The residue is dissolved in a little methanol andthe product is precipitated with diethyl ether. The solid is filteredoff with suction, washed repeatedly with diethyl ether and dried underreduced pressure.

Alternatively the workup may take place as follows: followingevaporation to dryness, the residue is taken up in water and washedtwice with ethyl acetate. The organic phase is discarded and the aqueousphase is neutralized with saturated sodium hydrogen carbonate solutionand again extracted three times with ethyl acetate. The organic phasesof the final extraction are dried over sodium sulfate or magnesiumsulfate, decanted and evaporated to dryness.

In accordance with general instructions B it is possible to obtain thefollowing compounds: Example Structure MW MS 17A

237.25 MS (ES+), m/z (%): 238 (M + H)⁺ 18A

223.23 MS (ES+), m/z (%): 224 (M + H)⁺

Example 19A Methyl 3-amino-3-(3-chlorophenyl)propionate

Methanol (110 ml) is cooled to −10° C. and slowly admixed with thionylchloride (12.0 g, 101.2 mmol). 3-Amino-3-(3-chlorophenyl)propionic acid(10.1 g, 50.6 mmol) is added and the mixture is stirred at roomtemperature overnight. The solution is concentrated to a high extent,under reduced pressure, and partitioned between ethyl acetate (100 ml)and saturated sodium hydrogen carbonate solution (200 ml). The pH of theaqueous phase is above 7. The aqueous phase is again extracted twicewith ethyl acetate (100 ml). The combined ethyl acetate phases are driedover sodium sulfate, filtered and concentrated.

Yield: 9.7 g (87%).

¹H NMR (300 MHz, CDCl₃): δ=7.37 (s, 1H), 7.30-7.20 (m, 3H), 4.40 (t,1H), 3.68 (s, 3H), 2.67-2.60 (m, 2H).

Example 20A Methyl (S)-3-amino-3-phenylpropionate

2.3 g (11.65 mmol) of (S)-3-amino-3-phenylpropionic acid are introducedin 100 ml of methanol and admixed with a catalytic amount ofconcentrated sulfuric acid (0.02 eq.). The reaction mixture is heated atreflux for 24 h and then concentrated. The crude product can be usedwithout further purification in the next stage.

Yield: 2.7 g (65%).

¹H NMR (300 MHz, d₆-DMSO): δ=8.50 (s, 2H), 7.52-7.37 (m, 5H), 4.61 (t,1H), 3.58 (s, 3H), 3.13 (dd, 1H), 2.98 (dd, 1H).

MS (ES+): m/z (%)=180 (M+H)⁺ (100).

General instructions C: Reaction of 3-amino-3-phenylpropionic acid alkylesters with carboxylic acids

The carboxylic acid (1.3-1.5 eq.) is introduced in dichloromethane(about 0.1 mol/l) at 0° C. and admixed with 1.3-1.5 eq. of HATU. Thismixture is admixed first with a solution of the3-amino-3-phenylpropionic acid alkyl ester (1 eq.) in a 1:1 mixture ofdichloromethane and N,N-dimethylformamide (about 0.1 mol/l) andsubsequently dropwise, over a period of 1 h, with a solution ofdiisopropylethylamine (3.5 eq) in a 1:1 mixture of dichloromethane andN,N-dimethylformamide (about 1 mol/l). The mixture is stirred at 0° C.for 30 minutes and then at room temperature overnight. The reactionmixture is then concentrated and purified by means of RP-HPLC (mobilephase: water-acetonitrile, gradient).

Alternatively the reaction may also take place by the following method:

A solution of the 3-aminopropionic acid alkyl ester (1 eq.) in absolutedichloromethane or a mixture (5:1 to 1:1) of absolute dichloromethaneand N,N-di-methylformamide (about 0.1 to 0.3 mol/l) is admixed with thecarboxylic acid derivative (1.1-1.5 eq.), triethylamine (3 eq.), HOBt (3eq.) and finally 1.2 eq. of EDC. The reaction mixture is stirred at roomtemperature (2 h to overnight), before being concentrated under reducedpressure. The residue is taken up in ethyl acetate or dichloromethaneand the organic phase is washed with water, saturated sodiumhydrogencarbonate solution and saturated sodium chloride solution, driedover sodium sulfate, filtered and concentrated. The product can bepurified by chromatography on silica gel (mobile phases: mixtures ofcyclohexane/ethyl acetate or mixtures of dichloromethane and ethanol) orby RP-HPLC (mobile phases: variable gradients of water andacetonitrile), or alternatively by a combination of both methods.

Example 21A Methyl(3S)-3-phenyl-3-[(2-pyridinylcarbonyl)amino]propionate

Synthesis in accordance with general instructions C.

¹H NMR (300 MHz, d₆-DMSO): δ=9.37 (d, 1H), 8.67 (d, 1H), 8.05-7.95 (m,2H), 7.66-7.57 (m, 1H), 7.48-7.19 (m, 5H), 5.49 (br. q, 1H), 3.55 (s,3H), 3.19 (dd, 1H), 2.96 (dd, 1H).

MS (ES+): m/z (%)=285 (M+H)⁺ (35).

HPLC (method 5): R_(t)=3.63 min.

Example 22A Methyl(3S)-3-{[(6-fluoro-2-pyridinyl)carbonyl]amino}-3-phenylpropionate

Synthesis in accordance with general instructions C.

¹H NMR (300 MHz, d₆-DMSO): δ=9.23 (d, 1H), 8.21-8.15 (m, 1H), 7.96-7.92(m, 1H), 7.45-7.20 (m, 6H), 5.46 (q, 1H), 3.55 (s, 3H), 3.18 (dd, 1H),2.96 (dd, 1H).

MS (ES+): m/z (%)=325 (M+Na)⁺ (60).

HPLC (method 14): R_(t)=4.35 min.

In accordance with general instructions C it is possible to obtain thefollowing compounds: Example Structure MW MS 23A

342.35 MS (ES+), m/z (%): 343 (M + H)⁺ 24A

360.34 MS (ES+), m/z (%): 361 (M + H)⁺ 25A

328.32 MS (ES+), m/z (%): 329 (M + H)⁺ 26A

312.37 MS (ES+), m/z (%): 313 (M + H)⁺

General instructions D: Hydrolysis of the propionic acid alkyl esters

The propionic acid alkyl ester is introduced to a vessel in a 3:1mixture of ethanol and water (about 0.1-0.15 mol/l) and 5 eq. of 40%strength sodium hydroxide solution are added. The reaction mixture isstirred at room temperature for 24 h, acidified with dilute hydrochloricacid (to a pH of about 3) and concentrated. The residue is taken up inethyl acetate and washed with saturated aqueous sodium chloridesolution. The organic phase is dried over magnesium sulfate, filteredand concentrated. The product obtained can be used without furtherpurification in the next stage.

An alternative option is to use the following method:

The propionic acid alkyl ester is introduced to a vessel in a 1:1mixture of dioxane and water (about 0.1-0.15 mol/l) and 3 eq. of asolution of potassium hydroxide in methanol (100 mg/ml) are added. Thereaction mixture is stirred at room temperature for 2 h and thenconcentrated. The residue is taken up in water and acidified with dilutehydrochloric acid. The aqueous phase is extracted three times with a 1:1mixture of dichloromethane and ethyl acetate. The combined organicphases are dried over sodium sulfate, filtered and concentrated. Theproduct obtained can be used without further purification in the nextstage.

Example 27A (3S)-3-Phenyl-3-[(2-pyridinylcarbonyl)amino]propionic acid

Synthesis in accordance with general instructions D.

¹H NMR (300 MHz, d₆-DMSO): δ=12.22 (s, 1H), 9.30 (d, 1H), 8.68 (d, 1H),8.05-7.95 (m, 2H), 7.66-7.58 (m, 1H), 7.46-7.19 (m, 5H), 5.45 (q, 1H),3.04 (dd, 1H), 2.87 (dd, 1H).

MS (ES−): m/z (%)=269 (M−H)⁻ (100).

HPLC (method 5): R_(t)=3.12 min.

Example 28A(3S)-3-{[(6-Fluoro-2-pyridinyl)carbonyl]amino}-3-phenylpropionic acid

Synthesis in accordance with general instructions D.

MS (ES−): m/z (%)=287 (M−H)⁻ (100).

HPLC (method 13): R_(t)=3.61 min.

In accordance with general instructions D it is possible to obtain thefollowing compounds: Example Structure MW MS HPLC 29A

328.32 MS (ES+), m/z (%): 329 (M + H)⁺ 30A

346.31 MS (ES−), m/z (%): 345 (M − H)⁻ HPLC (method 9): R_(t) = 3.69 min31A

314.3  MS (ES+), m/z (%): 315 (M + H)⁺ 32A

284.31 MS (ES+), m/z (%): 285 (M + H)⁺ HPLC (method 9): R_(t) = 3.82 min

The propionic acid derivatives obtained in this way can be reacted inaccordance with the instructions described below (reaction of3-[2-aminoalkanoyl]-2,5-pyrrolidinedione hydrochloride derivatives withcarboxylic acid derivatives).

General instructions E: Preparation of N-tert-butoxycarbonyl-protectedbeta-amino acids

The beta-amino acid (1 eq.) [synthesis in accordance with instructionsknown from the literature (e.g., S. Rault, P. Dallemagne, M. Robba,Bull. Soc. Chim. Fr., 1987, 1079-1083; L. Lázár, T. Martinek, G. Bemath,F. Fülöp, Synth. Comm., 1998, 28, 219-224)] is introduced in water(concentration about 0.3-1 mol/l) and admixed with triethylamine (1.5-3eq.). Then a solution of2-(tert-butoxycarbonyloximino)-phenylacetonitrile (1.1 eq.) in dioxane(0.3-1 mol/l) is added. The reaction mixture is stirred at roomtemperature for 3 h, diluted with water and washed with diethyl ether.The aqueous phase is acidified with 5% strength citric acid (to a pH ofabout 2) and extracted three times with ethyl acetate. The combinedorganic phases are washed with saturated sodium chloride solution, driedover sodium sulfate, filtered and concentrated. The crude product can ifdesired be recrystallized from ethyl acetate/n-hexane.

In accordance with general instructions E it is possible to obtain thefollowing compounds: Example Structure MW MS HPLC 33A

310.3  MS (ES+), m/z (%): 311 (M + H)⁺ HPLC (method 8): R_(t) = 3.87 min34A

323.34 MS (ES+), m/z (%): 324 (M + H)⁺ HPLC (method 8): R_(t) = 2.39 min35A

323.39 MS (ES−), m/z (%): 322 (M − H)⁻ HPLC (method 14): R_(t) = 4.35min

Example 36A (3S)-3-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid

2.82 g (17 mmol) of (S)-3-amino-3-phenylpropionic acid are slurred in 60ml of dioxane and at 0° C. 4.1 g (18.8 mmol) of di-tert-butyldicarbonate (Boc anhydride) and 43 ml of a 1N sodium hydroxide solutionin water are added to the slurry. The reaction mixture is stirred at 0°C. for 30 minutes and then at room temperature for 3 h. Subsequently thereaction mixture is concentrated and the residue is taken up inmethylene chloride. The organic phase is washed with 1N hydrochloricacid and saturated sodium chloride solution, dried over magnesiumsulfate and concentrated. The crude product (3.12 g) can be reactedfurther without additional purification.

MS (ES−): m/z (%)=264 (M−H)⁻ (100).

HPLC (method 14): R_(t)=3.89 min.

General instructions F: Acylation of3-[2-aminoalkanoyl]-2,5-pyrrolidinedione hydrochloride derivatives withcarboxylic acid derivatives

A solution of carboxylic acid derivative (1.2-1.5 eq.) in absolutedichloromethane or a mixture (5:1 to 1:1) of absolute dichloromethaneand N,N-dimethylformamide (about 0.1 to 0.3 mol/l) is admixed at 0° C.first with an equimolar amount of HATU and then with the3-[2-aminoalkanoyl]-2,5-pyrrolidinedione hydrochloride derivative (1eq., optionally as a solution in N,N-dimethylformamide ordichloromethane/N,N-dimethylformamide mixtures). Subsequently at 0° C. asolution of 2.5-3.5 eq. of diisopropylethylamine in a 1:1 mixture ofabsolute dichloromethane and N,N-dimethylformamide (0.2-1 mol/l) isadded dropwise over a period of 1 h. After the end of the addition thereaction mixture is stirred at 0° C. for 30 minutes more and then atroom temperature overnight, before being concentrated under reducedpressure. The product can be obtained by chromatography on silica gel(mobile phases: mixtures of cyclohexane/ethyl acetate or mixtures ofdichloromethane and ethanol) or by RP-HPLC (mobile phases: variablegradients of water and acetonitrile), or alternatively by a combinationof both methods.

Alternatively the reaction may also take place by the following method:

A solution of the 3-[2-aminoalkanoyl]-2,5-pyrrolidinedione hydrochloridederivative (1 eq.) in absolute dichloromethane or a mixture (5:1 to 1:1)of absolute dichloromethane and N,N-dimethylformamide (about 0.1 to 0.3mol/l) is admixed with the carboxylic acid derivative (1.1-1.5 eq.),triethylamine (3 eq.), HOBt (3 eq.) and finally 1.2 eq. of EDC. Thereaction mixture is stirred at room temperature (2 h to overnight)before being concentrated under reduced pressure. The residue is takenup in ethyl acetate or dichloromethane and the organic phase is washedwith water, saturated sodium hydrogencarbonate solution and saturatedsodium chloride solution, dried over sodium sulfate, filtered andconcentrated. The product can be purified by chromatography on silicagel (mobile phases: mixtures of cyclohexane/ethyl acetate or mixtures ofdichloromethane and ethanol) or by RP-HPLC (mobile phases: variablegradients of water and acetonitrile), or alternatively by a combinationof both methods.

Example 37A tert-Butyl((S)-2-{(S)-2-methyl-1-[1-((3R,4S)-4-methyl-2,5-dioxo-pyrrolidin-3-yl)-methanoyl]-propylcarbamoyl}-1-phenylethyl)carbamate

Synthesis in accordance with general instructions F.

¹H-NMR (400 MHz, d₆-DMSO): δ=11.45 (s, 1H), 7.98 (d, 1H), 7.31-7.24 (m,5H), 7.20 (br. s, 1H), 4.88-4.82 (br. s, 1H), 4.69 (br. s, 1H), 3.98 (d,1H), 2.95-2.89 (m, 1H), 2.77-2.69 (m, 1H), 2.51-2.44 (m, 1H), 2.35-2.29(m, 1H), 1.10 (d, 3H), 0.85 (d, 3H), 0.78 (d, 3H).

MS (ES+): m/z (%)=460 (M+H⁺) (100).

HPLC (method 6): R_(t)=3.90 min.

In accordance with general instructions F it is possible to obtain thefollowing compounds: Example Structure MW MS HPLC 38A

517.58 MS (ES+), m/z (%): 518 (M + H)⁺ HPLC (method 8): R_(t) = 2.60 min39A

517.62 MS (ES+), m/z (%): 518 (M + H)⁺ HPLC (method 14): R_(t) = 4.42min 40A

504.54 MS (ES−), m/z (%): 503 (M − H)⁻ HPLC (method 6): R_(t) = 3.99 min

General instructions G: Deblocking of Boc-protected derivatives

The tert-butyloxycarbonyl (BOC) protected amine derivative (optionallyas a solution in dioxane) is admixed at 0° C. or room temperature with4N hydrochloric acid solution in 1,4-dioxane (about 0.1 mol/l) andstirred at room temperature for 2 to 24 h before being concentratedunder reduced pressure. The residue can be reacted further withoutadditional purification or if desired is treated with dichloromethaneand diethyl ether. The precipitated crystals are filtered off withsuction and dried under a high vacuum. This gives the product as thehydrochloride.

Example 41A(S)-3-Amino-{(S)-2-methyl-1-[1-((3R,4S)-4-methyl-2,5-dioxopyrrolidin-3-yl)-methanoyl]-propyl}-3-phenylpropionamidehydrochloride

Synthesis in accordance with general instructions G.

¹H-NMR (200 MHz, d₆-DMSO): δ=11.49 (br. s, 1H), 8.5 (br. s, about 3H),7.54-7.32 (m, 5H), 4.69-4.55 (m, 2H), 3.89 (d, 1H), 3.06-2.80 (m, 3H),2.39-2.25 (m, 1H), 1.01 (d, 3H), 0.81 (d, 3H), 0.75 (d, 3H).

MS (ES+): m/z (%)=360 (M+H)⁺ (100).

HPLC (method 4): R_(t)=1.44 min.

In accordance with general instructions G it is possible to obtain thefollowing compounds: Example Structure MW MS HPLC 42A

417.46 MS (ES−), m/z (%): 416 (M − H)⁻ HPLC (method 5): R_(t) = 2.23 min43A

417.51 MS (ES−), m/z (%): 416 (M − H)⁻ HPLC (method 9): R_(t) = 2.97 min44A

404.42

In the same way as for Example 1A the following compounds are obtainedby reacting (3S)-3-methyldihydro-2,5-furandione with the correspondingprimary amines, hydroxylamine derivatives or hydrazine derivatives. Thecrude products can be purified by RP-HPLC (mobile phase:water-acetonitrile, gradient). Example Structure MW MS HPLC 45A

219.24 HPLC (method 6): R_(t) = 3.37 min 46A

156.18 MS (ESI+), m/z: 157 (M + H)⁺ HPLC (method 19): R_(t) = 2.62 min47A

157.17 MS (DCI), m/z: 175 (M + NH₄)⁺ HPLC (method 20): R_(t) = 1.70 min48A

228.25 MS (DCI), m/z: 246 (M + NH₄)⁺ HPLC (method 20): R_(t) = 2.09 min49A

143.14 MS (ESI+), m/z: 144 (M + H)⁺ 50A

276.29 MS (DCI), m/z: 294 (M + NH₄)⁺ HPLC (method 21): R_(t) = 2.80 min

General instructions J: Reaction of N-tert-butoxycarbonyl-protectedamino acids with 2,5-pyrrolidinedione derivatives

The N-tert-butoxycarbonyl-protected amino acid (1 eq.) andN,N-carbonyldiimidazole (1.1 eq.) are stirred in tetrahydrofuran (about0.1-1 mol/l) at room temperature for 2 h. The 2,5-pyrrolidinedione (1eq.) is then added to this mixture and the total mixture is addeddropwise over the course of 30 minutes to a 1 molar solution of lithiumhexamethyldisilazide (2 eq.) in THF, which is cooled at −65° C. Afterthe end of the addition stirring is continued at −65° C. for 15 minutesmore, and then saturated aqueous ammonium chloride solution is added.After the reaction mixture has been warmed to room temperature it isdiluted with diethyl ether and the organic phase is washed withsaturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered and subsequently concentrated. The crude product ispurified by RP-HPLC (mobile phase: water-acetonitrile, gradient).

In accordance with general instructions J it is possible by reacting thecorresponding N-tert-butoxycarbonyl-protected amino acids (for thepreparation of non-natural alpha-amino acids see, for example, A. A.Cordi et al., J. Med. Chem. 2001, 44, 787-805; K. Mai, G. Patil,Tetrahedron Lett. 1984, 25, 4583-4586; N. A. Hassan, E. Bayer, J. C.Jochims, J. Chem. Soc., Perkin Trans. 1 1998, 3747-3757; for thetert-butoxycarbonyl protection see, e.g., T. W. Greene, P. G. M. Wuts,Protective Groups in Organic Synthesis, 3^(rd) Edt. 1999, J. Wiley &Sons, Inc.) with 2,5-pyrrolidinediones to obtain the followingderivatives: Example Structure MW MS HPLC 51A

444.53 MS (ES−), m/z: 443 (M − H)⁻ HPLC (method 18): R_(t) = 4.11 min)52A

432.51 MS (ES−), m/z: 431 (M − H)⁻ HPLC (method 6): R_(t) = 4.88 min)53A

432.51 MS (ES−), m/z: 431 (M − H)⁻ HPLC (method 13): R_(t) = 5.08 min)54A

446.54 MS (ES−), m/z: 445 (M − H)⁻ HPLC (method 17): R_(t) = 4.42 min)55A

352.43 MS (ES−), m/z: 351 (M − H)⁻ HPLC (method 14): R_(t) = 4.61 min)56A

434.49 MS (ES−), m/z: 433 (M − H)⁻ HPLC (method 17): R_(t) = 3.98 min)57A

454.52 MS (ES−), m/z: 453 (M − H)⁻ HPLC (method 22): R_(t) = 4.41 min)58A

355.43 MS (ES+), m/z: 378 (M + Na)⁺ HPLC (method 19): R_(t) = 4.12 min)59A

356.42 MS (ES−), m/z: 355 (M − H)⁻ HPLC (method 20): R_(t) = 3.64 min)60A

427.50 MS (ES−), m/z: 426 (M − H)⁻ HPLC (method 20): R_(t) = 3.73 min)61A

342.39 MS (ES−), m/z: 341 (M − H)⁻ HPLC (method 19): R_(t) = 4.18 min)62A

381.47 MS (ES−), m/z: 380 (M − H)⁻ HPLC (method 21): R_(t) = 3.43 min)63A

475.54 MS (ES−), m/z: 474 (M − H)⁻ HPLC (method 20): R_(t) = 3.91 min)64A

501.58 MS (ES−), m/z: 500 (M − H)⁻ HPLC (method 21): R_(t) = 3.93 min)65A

453.53 MS (ES−), m/z: 452 (M − H)⁻ HPLC (method 21): R_(t) = 3.61 min)66A

430.51 MS (ES+), m/z: 453 (M + Na)⁺ HPLC (method 20): R_(t) = 4.32 min)

In accordance with general instructions A it is possible to obtain thefollowing compounds: Example Structure MW MS HPLC 67A

326.39 MS (ES−), m/z: 325 (M − H)⁻ HPLC (method 5): R_(t) = 3.91 min)68A

326.39 MS (ES−), m/z: 325 (M − H)⁻ HPLC (method 12): R_(t) = 2.88 min)69A

340.42 MS (ES−), m/z: 339 (M − H)⁻ HPLC (method 17): R_(t) = 3.59 min)70A

328.26 MS (ES+), m/z: 351 (M + Na)⁺ HPLC (method 20): R_(t) = 3.18 min)71A

338.40 MS (ES−), m/z: 337 (M − H)⁻ HPLC (method 17): R_(t) = 3.57 min)72A

324.38 MS (ES−), m/z: 323 (M − H)⁻ HPLC (method 19): R_(t) = 4.02 min)73A

350.41 MS (ES−), m/z: 349 (M − H)⁻ HPLC (method 18): R_(t) = 3.66 min)

Compound 73A was formed in the course of the reaction of compound 57A.

General instructions K: Deblocking of benzyloxycarbonyl-protectedhydrazine derivatives

The benzyloxycarbonyl-protected hydrazine derivative (1 eq.) isdissolved in methanol or ethanol (about 0.05 mol/l), a catalytic amountof palladium-on-carbon (10%) is added and the mixture is stirred under ahydrogen atmosphere (atmospheric pressure) for 3-4 h. The reactionmixture is then filtered and concentrated. The crude product can bereacted without further purification.

In accordance with general instructions K is it possible to obtain thefollowing compounds: Example Structure MW MS HPLC 74A

341.41 MS (ES−), m/z: 340 (M − H)⁻ HPLC (Methode 19): R_(t) = 4.00 min)75A

367.44 MS (ES−), m/z: 366 (M − H)⁻ HPLC (Methode 20): R_(t) = 3.47 min)

General instructions L: Deblocking of Boc-protected derivatives

The tert-butyloxycarbonyl (BOC)-protected amine derivative (optionallyas a solution in dioxane) is admixed with a 4N solution of hydrochloricacid in 1,4-dioxane (about 0.1 mol/l) and stirred at room temperaturefor 2-24 h before being concentrated under reduced pressure. The residuecan be reacted further without additional purification or if desired istreated with dichloromethane and diethyl ether. The precipitatedcrystals are filtered off with suction and dried under a high vacuum.The product is obtained as the hydrochloride.

In accordance with general instruction L it is possible to obtain thefollowing compounds: Exam- ple Structure MW 76A

238.29 77A

226.28 78A

226.28 79A

240.30 80A

252.32 81A

318.38 82A

228.25 83A

250.30 84A

255.32 85A

256.30 86A

227.27 87A

242.28 88A

281.36 89A

241.29 90A

267.33 91A

253.30 92A

224.26

In accordance with general working instructions B it is possible toprepare the following compounds: Example Structure MW MS HPLC 93A

180.2  MS (ES+), m/z: 180 (M + H)⁺ 94A

230.3  MS (ES+), m/z: 231 (M + H)⁺ HPLC (method 20): R_(t) = 1.70 min)95A

229.3  MS (ES+), m/z: 230 (M + H)⁺ HPLC (method 19): R_(t) = 1.75 min)96A

185.3  MS (ES+), m/z: 186 (M + H)⁺ 97A

169.2  MS (ES+), m/z: 170 (M + H)⁺ 98A

219.69 MS (ES+), m/z: 220 (M + H)⁺ 99A

264.14 MS (ES+), m/z: 264 (M + H)⁺

In accordance with general instructions C it is possible to obtain thefollowing compounds: Example Structure MW MS 100A

290.34 MS (ES+), m/z (%): 291 (M + H)⁺ 101A

274.28 MS (ES+), m/z (%): 275 (M + H)⁺ 102A

324.79 MS (ES+), m/z (%): 325 (M + H)⁺ 103A

369.24 MS (ES+), m/z (%): 369 (M + H)⁺

General instructions M: Reaction of 3-aminopropionic acid alkyl esterswith carbonyl chlorides

The 3-aminopropionic acid alkyl ester is introduced in dichloromethane(about 0.1-0.4 mol/l) at room temperature and 2-3 eq. ofdiisopropylethylamine and 1.2 eq. of the carbonyl chloride are added.The mixture is stirred at room temperature for 2-3 h. Then water isadded to the reaction mixture and the organic phase is separated off,dried over sodium sulfate, filtered and concentrated. The residue can berecrystallized from dichloromethane and diethyl ether or purified bymeans of chromatography on silica gel (mobile phase: mixtures ofdichloromethane and ethyl acetate).

In accordance with general instructions M it is possible to obtain thefollowing compounds: Example Structure MW MS 104A

385.38 MS (ES+), m/z (%): 386 (M + H)⁺ 105A

355.39 MS (ES+), m/z (%): 356 (M + H)⁺

In accordance with general instructions D it is possible to obtain thefollowing compounds: Example Structure MW MS HPLC 106A

276.32 MS (ES+), m/z (%): 277 (M + H)⁺ HPLC (method 9): R_(t) = 3.55 min107A

260.25 MS (ES+), m/z (%): 261 (M + H)⁺ HPLC (method 9): R_(t) = 3.43 min108A

310.76 MS (ES+), m/z (%): 311 (M + H)⁺ HPLC (method 9): R_(t) = 3.92 min109A

355.21 MS (ES+), m/z (%): 355 (M + H)⁺ HPLC (method 9): R_(t) = 3.89 min110A

371.35 MS (ES+), m/z (%): 372 (M + H)⁺ HPLC (method 9): R_(t) = 3.64 min111A

327.34 MS (ES+), m/z (%): 328 (M + H)⁺

The propionic acid derivatives obtained in this way can be reacted inaccordance with the general instructions F described below (acylation of3-[2-aminoalkanoyl]-2,5-pyrrolidinedione hydrochloride derivatives withcarboxylic acid derivatives).

In accordance with general instructions E it is possible to obtain thefollowing compounds: Example Structure MW MS HPLC 112A

323.35 HPLC (method 9): R_(t) = 3.96 min 113A

315.37 MS (ESI−), m/z: 314 (M − H)⁻ HPLC (method 21): R_(t) = 3.21 min114A

316.36 MS (ESI+), m/z: 317 (M + H)⁺ HPLC (method 19): R_(t) = 3.47 min115A

295.33 MS (ESI+), m/z: 296 (M + H)⁺ HPLC (method 20): R_(t) = 3.00 min116A

325.36 HPLC (method 9): R_(t) = 3.76 min 117A

266.30 MS (DCI), m/z: 167 (M − 100 + H)⁺ HPLC (method 9): R_(t) = 1.92min 118A

309.32 MS (ESI−), m/z: 308 (M − H)⁻ HPLC (method 13): R_(t) = 3.69 min

In accordance with general instructions F it is possible to obtain thefollowing compounds: Example Structure MW MS HPLC 119A

517.58 MS (ESI+), m/z: 518 (M + H)⁺ HPLC (method 16): R_(t) = 2.89 min120A

485.58 MS (ESI−), m/z: 484 (M − H)⁻ HPLC (method 20): R_(t) = 3.72 min121A

487.59 MS (ESI+), m/z: 488 (M + H)⁺ HPLC (method 17): R_(t) = 3.73 min122A

510.59 MS (ESI−), m/z: 509 (M − H)⁻ HPLC (method 19): R_(t) = 3.99 min123A

509.61 MS (ESI−), m/z: 508 (M − H)⁻ HPLC (method 20): R_(t) = 3.77 min124A

519.60 MS (ESI−), m/z: 518 (M − H)⁻ HPLC (method 18): R_(t) = 3.36 min125A

489.57 MS (ESI−), m/z: 488 (M − H)⁻ HPLC (method 19): R_(t) = 4.19 min126A

489.57 MS (ESI−), m/z: 488 (M − H)⁻ HPLC (method 20): R_(t) = 3.36 min127A

474.56 MS (ESI−), m/z: 473 (M − H)⁻ HPLC (method 19): R_(t) = 2.55 min128A

460.53 MS (ESI+), m/z: 461 (M + H)⁺ HPLC (method 5): R_(t) = 2.86 min129A

503.56 MS (ESI+), m/z: 504 (M + H)⁺ HPLC (method 14): R_(t) = 4.05 min

In accordance with general instructions G it is possible to obtain thefollowing compounds: Example Structure MW MS HPLC 130A

417.47 131A

385.47 MS (ESI−), m/z: 384 (M − H)⁻ HPLC (method 20): R_(t) = 1.90 min132A

387.48 133A

410.48 HPLC (method 9): R_(t) = 2.79 min 134A

409.49 MS (ESI−), m/z: 408 (M − H)⁻ HPLC (method 20): R_(t) = 2.14 and2.23 min 135A

419.48 HPLC (method 9): R_(t) = 2.80 min 136A

389.46 MS (ESI−), m/z: 388 (M − H)⁻ HPLC (method 19): R_(t) = 3.17 min137A

389.46 HPLC (method 9): R_(t) = 2.86 min 138A

374.44 139A

360.42 MS (ESI+), m/z: 361 (M + H)⁺ 140A

403.44 MS (ESI−), m/z: 402 (M − H)⁻ HPLC (method 14): R_(t) = 2.40 min

PREPARATION EXAMPLES General instructions H: Acylation of acylalkylaminosubstituted 3-[2-amino-alkanoyl]-2,5-pyrrolidinedione hydrochloridederivatives with carboxylic acid derivatives

A mixture of amine hydrochloride (1.0 eq.), carboxylic acid (1.2 to 1.3eq.) and HATU (1.2-1.4 eq.) in solution in absoluteN,N-dimethylformamide or in a 1:1 mixture of N,N-dimethylformamide anddichloromethane (0.02-0.2 mol/l) is admixed dropwise at 0° C. with a0.2-1.0 molar solution of diisopropylethylamine (2.5 to 3.5 eq.) inN,N-dimethylformamide or a 1:1 mixture of N,N-dimethylformamide anddichloromethane over a period of 1 h. When the addition is over thereaction mixture is stirred at 0° C. for another 30 minutes and at roomtemperature overnight, and then is concentrated under reduced pressure.The product can be obtained by chromatography on silica gel (mobilephases: mixtures of cyclohexane/ethyl acetate or mixtures ofdichloromethane and ethanol) or by RP-HPLC (mobile phases: variablegradients of water and acetonitrile), or alternatively by a combinationof both methods.

Alternatively the reaction may also take place. in accordance with thefollowing method:

A mixture of amine hydrochloride (1.0 eq.), carboxylic acid (1.2 to 1.3eq.), triethylamine (2.4-3 eq.) and HOBt (2.4-3 eq.) in absolutedichloromethane or in a mixture of N,N-dimethylformamide anddichloromethane (0.02-0.2 mol/l) is admixed finally with 1.2 eq. of EDC.The reaction mixture is stirred at room temperature (2 h to overnight)before being concentrated under reduced pressure. The residue is takenup in ethyl acetate or dichloromethane and the organic phase is washedwith water, saturated sodium hydrogencarbonate solution and saturatedsodium chloride solution, dried over sodium sulfate, filtered andconcentrated. The product can be purified by chromatography on silicagel (mobile phases: mixtures of cyclohexane/ethyl acetate or mixtures ofdichloromethane and ethanol) or by RP-HPLC (mobile phases: variablegradients of water and acetonitrile), or alternatively by a combinationof both methods.

In accordance with the above-described instructions for the acylation of3-[2-aminoalkanoyl]-2,5-pyrrolidinedione hydrochloride derivatives or ofacylalkylamino substituted 3-[2-aminoalkanoyl]-2,5-pyrrolidinedionehydrochloride derivatives with carboxylic acid derivatives it ispossible to obtain the following compounds.

Example 1N-{(1S)-3-[((1S)-1-{[(3R,4S)-1,4-Dimethyl-2,5-dioxo-3-pyrrolidinyl]carbonyl}-2-methylpropyl)amino]-3-oxo-1-phenylpropyl}-2-pyridinecarboxamide

¹H-NMR (200 MHz, d₆-DMSO): δ=9.59 (d, 1H), 8.65 (d, 1H), 8.21 (d, 1H),7.98 (d, 2H), 7.61 (q, 1H), 7.42-7.16 (m, 5H), 5.48-5.32 (m, 1H), 4.76(dd, 1H), 3.99 (d, 1H), 3.20-2.92 (m, 2H), 2.82 (s, 3H), 2.61 (dd, 1H),2.32-2.13 (m, 1H), 1.13 (d, 3H), 0.65 (d, 3H), 0.59 (d, 3H).

MS (ES+): m/z (%)=479 (M+H)⁺ (80).

HPLC (method 5): R_(t)=3.79 min.

Example 26-Fluoro-N-{(1S)-3-[((1S)-2-methyl-1-{[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]-carbonyl}propyl)amino]-3-oxo-1-phenylpropyl}-2-pyridinecarboxamide

¹H-NMR (300 MHz, d₆-DMSO): δ=11.31 (s, 1H), 9.32 (d, 1H), 8.22-8.10 (m,2H), 7.95-7.90 (m, 1H), 7.45-7.18 (m, 6H), 5.43-5.33 (m, 1H), 4.70 (dd,1H), 4.02 (d, 1H), 3.15 (dd, 1H), 3.01-2.90 (m, 1H), 2.62 (dd, 1H),2.30-2.18 (m, 1H), 1.10 (d, 3H), 0.62 (d, 3H), 0.59 (d, 3H).

MS (ES−): m/z (%)=481 (M−H)⁻ (100).

HPLC (method 3): R_(t)=4.19 min.

Example 3N-{(1S)-3-[((1S)-2-Methyl-1-{[(3R,4S)₄-methyl-2,5-dioxo-3-pyrrolidinyl]-carbonyl}propyl)amino]-3-oxo-1-phenylpropyl}-2-pyridinecarboxamide

¹H-NMR (300 MHz, d₆-DMSO): δ=11.32 (s, 1H), 9.53 (d, 1H), 8.69-8.65 (m,1H), 8.15 (d, 1H), 8.02-7.98 (m, 2H), 7.63-7.57 (m, 1H), 7.40-7.18 (m,5H), 5.45-5.35 (m, 1H), 4.67 (dd, 1H), 4.00 (d, 1H), 3.12 (dd, 1H), 2.97(dd, 1H), 2.64 (dd, 1H), 2.29-2.15 (m, 1H), 1.10 (d, 3H), 0.60 (d, 3H),0.56 (d, 3H).

MS (ES+): m/z (%)=465 (M+H)⁺ (100).

HPLC (method 6): R_(t)=3.65 min.

Example 4N-{(1S)-3-[((1S)-2-Methyl-1-{[(3R,4S)₄-methyl-2,5-dioxo-3-pyrrolidinyl]-carbonyl}propyl)amino]-3-oxo-1-phenylpropyl}-3-quinolinecarboxamide

¹H-NMR (principal conformer) (300 MHz, d₆-DMSO): δ=11.31 (s, 1H),9.29-9.12 (m, 2H), 8.82-8.78 (m, 1H), 8.15-8.07 (m, 3H), 7.90-7.82 (m,1H), 7.72-7.68 (m, 1H), 7.50-7.20 (m, 5H), 5.59-5.48 (m, 1H), 4.71 (dd,1H), 3.98 (d, 1H), 3.04-2.70 (m, 3H), 2.31-2.22 (m, 1H), 1.09 (d, 3H),0.79 (d, 3H), 0.68 (d, 3H).

MS (ES+): m/z (%)=515 (M+H)⁺ (100).

HPLC (method 6): R_(t)=3.52 min.

Example 5N-{(1S)-3-[((1S)-2-Methyl-1-{[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]-carbonyl}propyl)amino]-3-oxo-1-phenylpropyl}-1-isoquinolinecarboxamide

¹H-NMR (principal conformer) (400 MHz, d₆-DMSO): δ=11.34 (s, 1H), 9.56(d, 1H), 9.00 (d, 1H), 8.58 (d, 1H), 8.13 (d, 1H), 8.04 (d, 2H), 7.80(t, 1H), 7.70 (t, 1H), 7.45 (d, 2H), 7.34 (t, 2H), 7.23 (t, 1H),5.52-5.45 (m, 1H), 4.69 (dd, 1H), 4.00 (d, 1H), 3.10 (dd, 1H), 2.97-2.88(m, 1H), 2.70-2.62 (m, 1H), 2.21-2.12 (m, 1H), 1.10 (d, 3H), 0.59 (d,3H), 0.50 (d, 3H).

MS (ES+): m/z (%)=515 (M+H)⁺ (100).

HPLC (method 6): R_(t)=4.32 min.

Example 6N-{(1S)-3-[((1S)-2-Methyl-1-{[(3R,4S)₄-methyl-2,5-dioxo-3-pyrrolidinyl]-carbonyl}propyl)amino]-3-oxo-1-phenylpropyl}-4-phenyl-2-pyridinecarboxamide

¹H-NMR (200 MHz, d₆-DMSO): δ=11.36 (s, 1H), 9.67 (d, 1H), 8.72 (d, 1H),8.26-8.18 (m, 2H), 7.98-7.92 (m, 1H), 7.88-7.81 (m, 2H), 7.60-7.50 (m,3H), 7.45-7.20 (m, 5H), 5.50-5.38 (m, 1H), 4.75-4.68 (m, 1H), 4.02 (d,1H), 3.20-2.82 (m, 3H), 2.25-2.15 (m, 1H), 1.10 (d, 3H), 0.61 (d, 3H),0.57 (d, 3H).

MS (ES+): m/z (%)=541 (M+H)⁺ (100).

HPLC (method 14): R_(t)=4.88 min.

Example 76-Fluoro-N-{(1S)-3-[((1S,2S)-2-methyl-1-{[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]carbonyl}butyl)amino]-3-oxo-1-phenylpropyl}-2-pyridinecarboxamide

¹H-NMR (300 MHz, d₆-DMSO): δ=11.33 (s, 1H), 9.30 (d, 1H), 8.22-8.12 (m,2H), 7.95-7.91 (m, 1H), 7.45-7.20 (m, 6H), 5.45-5.35 (m, 1H), 4.67 (dd,1H), 4.03 (d, 1H), 3.17-3.09 (m, 1H), 2.97-2.88 (m, 1H), 2.62-2.54 (m,1H), 2.02-1.90 (m, 1H), 1.30-1.15 (m, 2H), 1.12 (d, 3H), 0.60 (d, 3H),0.56 (t, 3H).

MS (ES+): m/z (%)=497 (M+H)⁺ (100).

HPLC (method 12): R_(t)=2.95 min.

Example 8N-[(1S)-3-({(1S)-1-Cyclohexyl-2-[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]-2-oxoethyl}amino)-3-oxo-1-phenylpropyl]-6-fluoro-2-pyridinecarboxamide

¹H-NMR (principal conformer) (200 MHz, d₆-DMSO): δ=11.35 (s, 1H), 9.40(d, 1H), 8.27-8.10 (m, 2H), 7.99-7.90 (m, 1H), 7.50-7.18 (m, 6H),5.46-5.32 (m, 1H), 4.73 (dd, 1H), 4.08 (d, 1H), 3.26-3.10 (m, 1H),3.00-2.80 (m, 2H), 1.98-1.80 (m, 1H), 1.60-1.25 (m, 5H), 1.12 (d, 3H),1.10-0.65 (m, 5H).

MS (ES+): m/z (%)=523 (M+H)⁺ (100).

HPLC (method 12): R_(t)=3.12 min.

Example 9N-[(1S)-3-({1-Cyclopentyl-2-[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]-2-oxoethyl}amino)-3-oxo-1-phenylpropyl]-2-pyridinecarboxamide

¹H-NMR (2 diastereomers, approximately 2:1 ratio; a number ofconformers) (400 MHz, d₆-DMSO): δ=11.35+11.31 (2×s, 1H), 9.56+9.51-9.41(d+m, 1H), 8.71-8.63 (m, 1H), 8.60-8.42+8.30 (m+d, 1H), 8.02-7.92 (m,2H), 7.65-7.57 (m, 1H), 7.42-7.18 (m, 5H), 5.48-5.37 (m, 1H),4.65+4.454.28 (t+m, 1H), 3.99+3.87+3.80 (d+t+d, 1H), 3.13+3.07-2.98(dd+m, 1H), 2.95-2.80 (m, 1H), 2.70-2.58 (m, 1H), 2.36-2.18 (m, 1H),1.65-0.85 (m, 8H), 1.12+1.01 (2×d, 3H).

MS (ES+): m/z (%)=491 (M+H)⁺ (100).

HPLC (method 12): R_(t)=2.79 min.

Example 10(3S)-N-((1S)-2-Methyl-1-{[(3R,4S)₄-methyl-2,5-dioxo-3-pyrrolidinyl]carbonyl}-propyl)-3-phenyl-3-[(2-thienylacetyl)amino]propanamide

¹H-NMR (300 MHz, d₆-DMSO): δ=11.31 (s, 1H), 8.50 (d, 1H), 8.08 (d, 1H),7.34-7.18 (m, 6H), 6.95-6.90 (m, 1H), 6.89-6.85 (m, 1H), 5.25-5.16 (m,1H), 4.61 (dd, 1H), 3.91 (d, 1H), 3.66 (d, 2H), 2.90 (dd, 1H), 2.80-2.60(m, 2H), 2.32-2.23 (m, 1H), 1.07 (d, 3H), 0.81 (d, 3H), 0.75 (d, 3H).

MS (ES−): m/z (%)=482 (M−H)⁻ (100).

HPLC (method 5): R_(t)=3.72 min. Example Structure MW MS HPLC 11

478.55 MS (ES+), m/z (%): 479 (M + H)⁺ (100) HPLC (method 5) R_(t) =3.69 min 12

522.55 MS (ES+), m/z (%): 523 (M + H)⁺ (75) HPLC (method 9) R_(t) = 3.81min 13

514.58 MS (ES+), m/z (%): 515 (M + H)⁺ (100) HPLC (method 5) R_(t) =3.97 min 14

464.52 MS (ES+), m/z (%): 465 (M + H)⁺ (100) HPLC (method 5) R_(t) =3.01 min 15

483.59 MS (ES+), m/z (%): 506 (M + Na)⁺ (100) HPLC (method 5) R_(t) =3.74 min 16

482.51 MS (ES+), m/z (%): 505 (M + Na)⁺ (100) HPLC (method 6) R_(t) =3.48 min 17

482.51 MS (ES−), m/z (%): 481 (M − H+) (100) HPLC (method 6) R_(t) =3.46 min 18

478.55 MS (ES+), m/z (%): 479 (M + H)⁺ (45) HPLC (method 9) R_(t) = 4.03min 19

503.55 MS (ES+), m/z (%): 523 (M + Na)⁺ (100) HPLC (method 6) R_(t) =3.94 min 20

508.53 MS (ES+), m/z (%): 509 (M + H)⁺ (90) HPLC (method 9) R_(t) = 3.82min 21

518.57 MS (ES+), m/z (%): 519 (M + H)⁺ (100) HPLC (method 3) R_(t) =3.95 min 22

540.55 MS (ES+), m/z (%): 541 (M + H)⁺ (35) HPLC (method 9) R_(t) = 3.92min 23

520.63 MS (ES−), m/z (%): 519 (M − H)⁻ (100) HPLC (method 5) R_(t) = 4.6min 24

478.55 MS (ES−), m/z (%): 477 (M − H)⁻ (100) HPLC (method 5) R_(t) = 3.9min 25

530.58 MS (ES+), m/z (%): 531 (M + H)⁺ (100) HPLC (method 6) R_(t) =3.70 min 26

533.41 MS (ES+), m/z (%): 533 (M + H)⁺ (100) HPLC (method 6) R_(t) =4.20 min 27

566.96 MS (ES+), m/z (%): 567 (M + H)⁺ (100) HPLC (method 6) R_(t) =4.42 min 28

482.51 MS (ES+), m/z (%): 483 (M + H)⁺ (100) HPLC (method 11) R_(t) =2.66 min 29

544.60 MS (ES+), m/z (%): 545 (M + H)⁺ (100) HPLC (method 14) R_(t) =4.5 min 30

514.58 MS (ES−), m/z (%): 513 (M − H)⁻ (100) HPLC (method 14) R_(t) =4.40 min 31

498.96 MS (ES−), m/z (%): 497 (M − H)⁻ (100) HPLC (method 14) R_(t) =4.37 min 32

498.96 MS (ES+), m/z (%): 521 (M + Na)⁺ (100) HPLC (method 13) R_(t) =4.05 min 33

480.52 MS (ES+), m/z (%): 481 (M + H)⁺ (100) HPLC (method 14) R_(t) =3.65 min 34

478.55 MS (ES+), m/z (%): 479 (M + H)⁺ (100) HPLC (method 13) R_(t) =3.98 min 35

540.59 MS (ES−), m/z (%): 539 (M − H)⁻ (100) HPLC (method 11) R_(t) =2.73 min 36

522.55 MS (ES−), m/z (%): 521 (M − H)⁻ (100) HPLC (method 5) R_(t) =3.67 min 37

540.55 MS (ES+), m/z (%): 541 (M + H)⁺ (100) HPLC (method 9) R_(t) =3.75 min 38

540.55 MS (ES+), m/z (%): 541 (M + H)⁺ (100) HPLC (method 9) R_(t) =3.80 min 39

540.55 MS (ES+), m/z (%): 541 (M + H)⁺ (100) HPLC (method 14) R_(t) =4.12 min 40

527.51 MS (ES+), m/z (%): 528 (M + H)⁺ (100) HPLC (method 12) R_(t) =2.76 min 41

478.55 MS (ES+), m/z (%): 479 (M + H)⁺ (100) HPLC (method 5) R_(t) =2.64 min 42

483.59 MS (ES+), m/z (%): 484 (M + H)⁺ (100) HPLC (method 15) R_(t) =2.94 min 43

532.60 MS (ES+), m/z (%): 555 (M + Na)⁺ (100) HPLC (method 5) R_(t) =3.52 min 44

511.64 MS (ES+), m/z (%): 534 (M + Na)⁺ (100) HPLC (method 5) R_(t) =4.00 min

General instructions I: Solid-phase-supported synthesis

The aldehyde resin (Nova Biochem) (0.78 mmol/g) is suspended intoluene/trimethyl orthoformate (1:1 to 4:1), admixed with thecorresponding beta-amino acid methyl ester (2.5-3 eq) at roomtemperature and shaken overnight. The resin is washed twice withN,N-dimethylformamide, suspended in N,N-dimethylformamide and admixedwith tetrabutylammonium borohydride (2-5 eq) at room temperature. After30 minutes of shaking at room temperature the reaction mixture is slowlyadmixed with glacial acetic acid (100 eq) at from 40° C. to roomtemperature, optionally warmed to room temperature again and shaken forat least 1 h. The resin is washed repeatedly with water, methanol,dichloromethane/10% N,N-diisopropylethylamine, methanol, dichloromethaneand diethyl ether and dried. The resin is suspended in dichloromethaneand shaken with N,N-diisopropylethylamine (10-20 eq) and with thecorresponding carbonyl chloride (5 eq) at room temperature for 1-2 h.The resin is washed repeatedly with methanol, N,N-dimethylformamide,methanol, dichloromethane and diethyl ether and dried. For hydrolysisthe resin is admixed with a solution of potassium hydroxide (30 eq) inmethanol/dioxane (1:2, 30 mg potassium hydroxide/ml solution) and shakenat RT for 3 h. Subsequently the resin is washed with water, methanol,dichloromethane/glacial acetic acid, dichloromethane,dichloromethane/N,N-diisopropylethylamine, methanol,N,N-dimethylformamide, methanol, dichloromethane and diethyl ether. Theresin is shaken with (benzotriazol-1-yloxy)bisdimethylaminomethyliumfluoroborate (5 eq) and N,N-diisopropylethylamine (20 eq) inN,N-dimethylacetamide at RT for 1 h, washed twice withN,N-dimethylacetamide, admixed with a freshly prepared solution of(3R,4S)-3-[(2S)-2-amino-3-methylbutanoyl]-4-methyl-2,5-pyrrolidinedionehydrochloride (1.5-2 eq) and N,N-diisopropylethylamine (20 eq) andshaken at RT for 3 h. Finally the resin is washed repeatedly withmethanol, N,N-dimethylformamide, water, N,N-dimethylformamide, methanol,dichloromethane and diethyl ether and dried. The resin is shaken withtrifluoroacetic acid or 50% strength trifluoroacetic acid indichloromethane at from RT to 50° C. for from 30 minutes to 3 h. Thecrude product solution is filtered, evaporated to dryness and purifed byreversed phase HPLC using a water/acetonitrile gradient. An alternativepossibility is chromatography on silica gel (mobile phases: mixtures ofdichloromethane and methanol).

Example 45N-{1-(3-Chlorophenyl)-3-[((1S)-2-methyl-1-{[(3R,4S)₄-methyl-2,5-dioxo-3-pyrrolidinyl]carbonyl}propyl)amino]-3-oxopropyl}-2-pyridinecarboxamide

¹H-NMR (2 diastereoisomers, ratio 1:1, 300 MHz, DMSO-d₆): δ=11.3 (d,1H), 9.64 (d, 0.5H), 9.45 (d, 0.5H), 8.70-8.62 (m, 1H), 8.28 (d, 0.5H),8.18 (d, 0.5H), 8.02-7.94 (m, 2H), 7.65-7.56 (m, 1H), 7.50-7.41 (m, 1H),7.38-7.21 (m, 3H), 5.48-5.32 (m, 1H), 4.69 (dd, 0.5H), 4.60 (dd, 0.5H),4.02 (d, 0.5H), 3.93 (d, 0.5H), 3.10-2.60 (m, 3H), 2.35-2.15 (m, 1H),1.15-1.03 (m, 3H), 0.75-0.54 (m, 6H).

MS (ES+): m/z (%)=499 (M+H)⁺ (100).

HPLC (method 6): R_(t)=3.95 min.

Example 46N-[(1S)-3-({(1S)-1-Cyclopentyl-2-[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]-2-oxoethyl}amino)-3-oxo-1-phenylpropyl]-4-phenyl-2-pyridinecarboxamide

¹H-NMR (300 MHz, d₆-DMSO): δ=11.33 (s, 1H), 9.59 (d, 1H), 8.74 (d, 1H),8.31 (d, 1H), 8.23 (s, 1H), 7.98-7.89 (m, 1H), 7.87-7.77 (m, 2H),7.59-7.19 (m, 8H), 5.50-5.38 (m, 1H), 4.62 (t, 1H), 3.99 (d, 1H),3.48-3.00 (m, 2H), 2.96-2.83 (m, 1H), 2.75-2.18 (m, 4H), 1.53-0.71 (m,5H), 1.08 (d, 3H).

MS (ES+): m/z=567 (M+H⁺).

HPLC (method 19): R_(t)=4.28 min.

Example 47N-[(1S)-3-({(1S)-1-Cyclopentyl-2-[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]-2-oxoethyl}amino)-3-oxo-1-phenylpropyl]-3-quinolinecarboxamide

¹H-NMR (300 MHz, d₆-DMSO): δ=11.34 (s, 1H), 9.32 (d, 1H), 9.22 (d, 1H),8.93 (d, 1H), 8.32 (d, 1H), 8.11 (d, 2H), 7.89 (dt, 1H), 7.72 (t, 1H),7.50-7.19 (m, 5H), 5.58-5.44 (m, 1H), 4.61 (t, 1H), 3.93 (d, 1H),3.77-3.55 (m, 1H), 3.10-2.21 (m, 5H), 1.60-0.96 (m, 6H), 1.09 (d, 3H).

MS (ESI+): m/z=541 (M+H⁺).

HPLC (method 19): R_(t)=4.04 min.

Example 48N-[(1S)-3-({(1S)-1-Cyclopentyl-2-[(3R,4S)₄-methyl-2,5-dioxo-3-pyrrolidinyl]-2-oxoethyl}amino)-3-oxo-1-phenylpropyl]-5-fluoro-1H-indole-2-carboxamide

¹H-NMR (200 MHz, d₆-DMSO): δ=11.66 (s, 1H), 11.37 (s, 1H), 8.83 (d, 1H),8.27 (d, 1H), 7.48-6.94 (m, 9H) 5.54-5.36 (m, 1H), 4.71-4.61 (m, 1H),3.98 (d, 1H), 3.28-3.19 (m, 1H), 3.01-2.11 (m, 6H), 1.54-0.97 (m, 5H),1.08 (d, 3H).

MS (ESI+): m/z=547 (M+H⁺).

HPLC (method 19): R_(t)=3.44 min. Example Structure MW MS HPLC 49

539.63 MS (ES+), m/z: 540 (M + H)⁺ HPLC (method 5): R_(t) = 4.22 min 50

507.54 MS (ES+), m/z: 508 (M + H)⁺ HPLC (method 5): R_(t) = 3.61 min 51

554.64 MS (ES+), m/z: 555 (M + H)⁺ HPLC (method 8): R_(t) = 2.72 min 52

478.55 MS (ES+), m/z: 479 (M + H)⁺ HPLC (method 5): R_(t) = 3.67 min 53

508.53 MS (ES+), m/z: 509 (M + H)⁺ HPLC (method 5): R_(t) = 2.45 and2.52 min 54

465.51 MS (ES+), m/z: 466 (M + H)⁺ 55

464.52 MS (ES+), m/z: 465 (M + H)⁺ HPLC (method 5): R_(t) = 3.02 min 56

506.60 MS (ES+), m/z: 507 (M + H)⁺ HPLC (method 5): R_(t) = 3.72 min 57

506.60 MS (ES+), m/z: 507 (M + H)⁺ HPLC (method 5): R_(t) = 3.62 min 58

546.45 MS (ES+), m/z: 546 (M + H)⁺ HPLC (method 8): R_(t) = 2.60 min 59

545.68 MS (ES+), m/z: 546 (M + H)⁺ HPLC (method 5): R_(t) = 4.65 min 60

569.65 MS (ES+), m/z: 570 (M + H)⁺ HPLC (method 5): R_(t) = 4.19 min 61

560.61 MS (ES+), m/z: 561 (M + H)⁺ HPLC (method 5): R_(t) = 3.28 min 62

470.55 MS (ES+), m/z: 471 (M + H)⁺ HPLC (method 5): R_(t) = 3.5 min 63

454.48 MS (ES+), m/z: 455 (M + H)⁺ HPLC (method 5): R_(t) = 3.4 min 64

504.99 MS (ES+), m/z: 505 (M + H)⁺ HPLC (method 5): R_(t) = 3.8 min 65

549.44 MS (ES+), m/z: 551 (M + H)⁺ HPLC (method 5): R_(t) = 3.8 min 66

565.58 MS (ES+), m/z: 566 (M + H)⁺ HPLC (method 5): R_(t) = 3.5 min 67

555.63 MS (ES−), m/z: 554 (M − H)⁻ HPLC (method 6): R_(t) = 4.28 min 68

553.61 MS (ES+), m/z: 554 (M + H)⁺ HPLC (method 6): R_(t) = 3.85 min 69

535.64 MS (ES+), m/z: 536 (M + H)⁺ HPLC (method 6): R_(t) = 4.34 min 70

570.64 MS (ES+), m/z: 571 (M + H)⁺ HPLC (method 5): R_(t) = 4.48 min 71

521.57 MS (ES+), m/z: 522 (M + H)⁺ HPLC (method 9): R_(t) = 4.05 min 72

521.57 MS (ES+), m/z: 522 (M + H)⁺ HPLC (method 5): R_(t) = 3.73 min 73

535.59 MS (ES−), m/z: 534 (M − H)⁻ HPLC (method 5): R_(t) = 3.71 min 74

551.64 MS (ES−), m/z: 550 (M − H)⁻ HPLC (method 5): R_(t) = 3.65 min 75

596.68 MS (ES+), m/z: 597 (M + H)⁺ HPLC (method 6): R_(t) = 3.78 min 76

480.52 MS (ES+), m/z: 481 (M + H)⁺ HPLC (method 5): R_(t) = 3.63 min 77

535.59 MS (ES+), m/z: 536 (M + H)⁺ HPLC (method 6): R_(t) = 3.76 min 78

542.61 MS (ES−), m/z: 541 (M − H)⁻ HPLC (method 5): R_(t) = 3.39 min 79

565.58 MS (ES+), m/z: 566 (M + H)⁺ HPLC (method 14): R_(t) = 4.19 min 80

483.50 MS (ES+), m/z: 484 (M + H)⁺ HPLC (method 9): R_(t) = 2.93 min 81

504.58 MS (ES+), m/z: 505 (M + H)⁺ HPLC (method 17): R_(t) = 3.57 min 82

540.55 MS (ES+), m/z: 563 (M + Na)⁺ HPLC (method 14): R_(t) = 4.25 min83

568.67 MS (ES+), m/z: 570 (M + H)⁺ HPLC (method 18): R_(t) = 3.96 min 84

502.57 MS (ES+), m/z: 503 (M + H)⁺ HPLC (method 20): R_(t) = 3.45 min 85

525.58 MS (ES+), m/z: 526 (M + H)⁺ HPLC (method 20): R_(t) = 3.55 min 86

507.59 MS (ES+), m/z: 508 (M + H)⁺ HPLC (method 20): R_(t) = 3.43 min 87

508.57 MS (ES+), m/z: 509 (M + H)⁺ HPLC (method 20): R_(t) = 3.60 min 88

476.53 MS (ES+), m/z: 477 (M + H)⁺ HPLC (method 20): R_(t) = 3.12 min 89

498.51 MS (ES+), m/z: 499 (M + H)⁺ HPLC (method 18): R_(t) = 3.35 min 90

532.57 MS (ES+), m/z: 533 (M + H)⁺ HPLC (method 19): R_(t) = 4.24 min 91

494.55 MS (ES+), m/z: 495 (M + H)⁺ HPLC (method 19): R_(t) = 3.47 min 92

542.56 MS (ES+), m/z: 543 (M + H)⁺ HPLC (method 20): R_(t) = 3.02 min 93

493.56 MS (ES+), m/z: 494 (M + H)⁺ HPLC (method 19): R_(t) = 4.06 min 94

544.63 MS (ES+), m/z: 545 (M + H)⁺ HPLC (method 20): R_(t) = 3.42 min 95

520.56 MS (ES+), m/z: 521 (M + H)⁺ HPLC (method 19): R_(t) = 4.17 min 96

581.46 MS (ES+), m/z: 583 (M + H)⁺ HPLC (method 18): R_(t) = 3.6 min 97

554.06 MS (ES+), m/z: 554 (M + H)⁺ HPLC (method 19): R_(t) = 4.17 min 98

547.63 MS (ES+), m/z: 548 (M + H)⁺ HPLC (method 19): R_(t) = 4.01 min 99

512.54 MS (ES+), m/z: 513 (M + H)⁺ HPLC (method 19): R_(t) = 4.04 min100 

488.54 MS (ES+), m/z: 489 (M + H)⁺ HPLC (method 20): R_(t) = 3.15 min101 

516.60 MS (ES+), m/z: 517 (M + H)⁺ HPLC (method 18): R_(t) = 3.5 min102 

538.55 MS (ES+), m/z: 539 (M + H)⁺ HPLC (method 18): R_(t) = 3.5 min103 

519.62 MS (ES+), m/z: 520 (M + H)⁺ HPLC (method 18): R_(t) = 3.5 min104 

587.62 MS (ES+), m/z: 588 (M + H)⁺ HPLC (method 18): R_(t) = 3.7 min105 

562.66 MS (ES+), m/z: 563 (M + H)⁺ HPLC (method 19): R_(t) = 2.42 min106 

543.62 MS (ES+), m/z: 544 (M + H)⁺ HPLC (method 18): R_(t) = 3.2 min107 

533.56 MS (ES+), m/z: 534 (M + H)⁺ HPLC (method 20): R_(t) = 2.45 min108 

597.99 MS (ES+), m/z: 598 (M + H)⁺ HPLC (method 18): R_(t) = 3.6 min109 

576.47 MS (ES+), m/z: 576 (M + H)⁺ HPLC (method 18): R_(t) = 3.5 min110 

528.61 MS (ES+), m/z: 529 (M + H)⁺ HPLC (method 18): R_(t) = 2.6 min111 

518.57 MS (ES+), m/z: 519 (M + H)⁺ HPLC (method 19): R_(t) = 2.26 min112 

527.58 MS (ES+), m/z: 528 (M + H)⁺ HPLC (method 19): R_(t) = 2.61 min113 

533.63 MS (ES+), m/z: 534 (M + H)⁺ HPLC (method 19): R_(t) = 2.55 min114 

479.53 MS (ES+), m/z: 480 (M + H)⁺ HPLC (method 20): R_(t) = 1.97 min115 

479.53 MS (ES+), m/z: 480 (M + H)⁺ HPLC (method 19): R_(t) = 1.82 minB) Evaluation of Physiological Activity

The suitability of the compounds of the invention for treating bacterialdiseases can be demonstrated in the following animal models:

Determination of the Minimum Inhibitory Concentration (MIC):

The MIC is determined in a liquid dilution test. Overnight cultures ofthe test organisms are diluted to a cell count of 10⁵ organisms per mlin Isosensitest medium (Difco, Irvine, USA) and are incubated withdilutions of the test substances (1:2 dilution stages). Exceptions arethe tests with S. pneumoniae G9A, which are conducted in BHI broth(Difco) plus 20% bovine serum, and with H. influenzae, which areconducted in BHI broth (Difco) plus 20% bovine serum, 10 μg/ml hemin and1% Isovitale (Becton Dickinson, New Jersey, USA).

The cultures are incubated at 37° C. for 18-24 hours; S. pneumoniae andH. influenzae in the presence of 8-10% CO₂.

Results:

The lowest concentration of each substance at which there is no longerany visible bacterial growth is defined as the MIC. The MICs in μmol/lof some compounds of the invention against a series of test organismsare listed by way of example in the table below. StaphylococcusHaemophilus influenzae Ex. No. aureus 133 Spain 7 2 15.63 7.81 4 15.6331.25 6 7.81 15.63 9 7.81 62.5 48 0.98 15.63 109 0.98 62.5Systemic Infection with S. aureus 133

S. aureus 133 cells are cultured overnight in BH broth (Oxoid, N.Y.,USA). The overnight culture is diluted 1:100 in fresh BH broth and spunat high speed for 3 hours. The bacteria in the logarithmic growth phaseare centrifuged off and washed 2× with buffered physiological salinesolution. Subsequently a photometer (Dr. Lange model LP 2W, Berlin,Germany) is used to establish a cell suspension in saline solution withan extinction of 50 units. Following a dilution step (1:15) thissuspension is mixed 1:1 with a 10% mucin suspension. 0.25 ml/20 g mouseof this infection solution is administered intraperitoneally. Thiscorresponds to a cell count of approximately 1×10E⁶ organisms/mouse. Theintraperitoneal or intravenous therapy is practiced 30 minutes followinginfection. Female CFW1 mice are used for the infection experiment. Thesurvival of the animals is recorded over 6 days.

C) Examples of Pharmaceutical Compositions

The substances of the invention can be converted into pharmaceuticalformulations as follows:

Tablet:

Composition:

100 mg of the compound from Example 1, 50 mg of lactose (monohydrate),50 mg of corn starch, 10 mg of polyvinylpyrolidone (PVP 25) (BASF,Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

Production:

The mixture of the compound of Example 1, lactose and starch isgranulated with a 5% strength solution (m/m) of the PVP in water. Thegranules are dried and then mixed with the magnesium stearate for 5minutes. This mixture is compressed using a conventional tablet press(see above for tablet format).

Oral Suspension:

Composition:

1000 mg of the compound from Example 1, 1000 mg of ethanol (96%), 400 mgof Rhodigel (xanthan gum) (FMC, USA) and 99 g of water.

10 ml of oral suspension correspond to a single dose of 100 mg of thecompound of the invention.

Production:

The Rhodigel is suspended in ethanol and the compound of Example 1 isadded to the suspension. The water is added with stirring. The mixtureis stirred for about 6 h until the Rhodigel has finished swelling.

Solution for Intravenous Administration:

Composition:

100-200 mg of the compound from Example 1, 15 g of polyethylene glycol400 and 250 g of injection-grade water.

Production:

The compound of Example 1 is dissolved together with polyethylene glycol400 in the water, with stirring. The solution is subjected to sterilefiltration (pore diameter 0.22 μm) and dispensed under asepticconditions into heat-sterilized infusion bottles. These bottles aresealed with infusion stoppers and crimped caps.

1. A compound of the formula

in which R¹ is heteroaryl, where heteroaryl can be substituted by 0, 1,2 or 3 substituents R¹⁻¹, the substituents R¹⁻¹ being selectedindependently of one another from the group consisting of halogen,alkyl, nitro, amino, alkylamino, cyano, trifluoromethyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, hydroxyl, alkoxy, aryloxy, benzyloxy,carboxyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonylamino,alkylaminocarbonyl and aminosulfonyl, or R¹ is aryl, where aryl issubstituted by 1, 2 or 3 substituents R¹⁻², the substituents R¹⁻² beingselected independently of one another from the group consisting ofhalogen, alkyl, nitro, amino, alkylamino, cyano, trifluoromethyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, alkoxy, aryloxy,benzyloxy, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonylamino,arylcarbonylamino, alkylaminocarbonyl and aminosulfonyl, or twosubstituents R¹⁻², together with the carbon atoms to which they areattached, form a cycloalkyl or heterocyclyl which can be substituted by0, 1 or 2 substituents R¹⁻²⁻¹, the substituents R¹⁻²⁻¹ being selectedindependently of one another from the group consisting of halogen,nitro, amino, trifluoromethyl, hydroxyl, alkyl and alkoxy, R² ishydrogen or methyl, R³ is hydrogen, hydroxyl, amino, C₁-C₃ alkyl,benzyl, C₁-C₃ alkoxy, benzyloxy, C₁-C₃ alkylamino, C₁-C₃alkylcarbonylamino, phenylcarbonylamino or benzylcarbonylamino, R⁴ ishydrogen or C₁-C₃ alkyl, R⁵ is halogen, trifluoromethyl,trifluoromethoxy, nitro, amino, alkylamino, hydroxyl, alkyl, alkoxy,carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, aryl orheteroaryl, or two substituents R⁵ together with the carbon atoms towhich they are attached form a cycloalkyl or heterocyclyl each of whichmay be substituted by 0, 1 or 2 substituents R⁵⁻¹, the substituents R⁵⁻¹being selected independently of one another from the group consisting ofhalogen, nitro, amino, trifluoromethyl, hydroxyl, alkyl and alkoxy, R⁶is alkyl, cycloalkyl, cycloalkenyl or heterocyclyl, it being possiblefor R⁶ to be substituted by 0, 1 or 2 substituents R⁶⁻¹, thesubstituents R⁶⁻¹ being selected independently of one another from thegroup consisting of halogen, nitro, amino, trifluoromethyl, hydroxyl,alkyl and alkoxy, n is a number 0, 1, 2 or 3, it being possible for theradicals R⁵ to be identical or different when n is 2 or 3, m is a number0, 1, 2, 3 or 4, A is aryl or heteroaryl, or a salt thereof, a solvatethereof or a solvate of a salt thereof.
 2. A compound according to claim1, characterized in that it corresponds to the formula

in which R¹ to R⁶, A, m and n have the same definition as in formula(I).
 3. A compound according to claim 1, characterized in that R¹ ispyridyl, imidazolyl, thienyl, furyl, oxadiazolyl, pyrazolyl, pyrazinyl,pyridazinyl, pyrimidinyl, quinolinyl or isoquinolinyl, where R¹ can besubstituted by 0, 1 or 2 substituents R¹⁻¹, the substituents R¹⁻¹ beingselected independently of one another from the group consisting ofhalogen, alkyl, amino, trifluoromethyl, phenyl and alkoxy, or R¹ isphenyl or naphthyl, where phenyl or naphthyl are substituted by 1, 2 or3 substituents R¹⁻², the substituents R¹⁻² being selected independentlyof one another from the group consisting of halogen, C₁-C₄ alkyl,dimethylamino, cyano, trifluoromethyl, 3- to 7-membered cycloalkyl, 5-or 6-membered heterocyclyl, phenyl, 5- or 6-membered heteroaryl, C₁-C₃alkoxy, phenyloxy, benzyloxy, phenylcarbonylamino and aminosulfonyl, ortwo substituents R¹⁻², together with the carbon atoms to which they areattached, form a 1,3-benzodioxole or a 1,4-benzodioxane, R² is hydrogen,R³ is hydrogen, amino, methyl, methoxy, ethoxy, methylamino ordimethylamino, R⁴ is methyl, R⁵ is fluoro, chloro, trifluoromethyl,C₁-C₄ alkoxy, methoxycarbonyl, C₁-C₄ alkyl, phenyl or pyridyl, or twosubstituents R⁵, together with the phenyl ring to which they areattached, form a 1,3-benzodioxole or a 1,4-benzodioxane, R⁶ is C₃-C₆alkyl or 3- to 6-membered cycloalkyl, n is a number 0, 1 or 2, and, if nis 2, the radicals R⁵ can be identical or different, m is a number 0, 1,2 or 3, and A is phenyl, naphthyl, pyridyl, thienyl, furanyl, quinolinylor isoquinolinyl.
 4. A compound according to claim 1, characterized inthat R¹ is pyridyl, thienyl, furyl, quinolinyl or isoquinolinyl, whereR¹ can be substituted by 0, 1 or 2 substituents R¹⁻¹, the substituentsR¹⁻¹ being selected independently of one another from the groupconsisting of halogen, C₁-C₄ alkyl, trifluoromethyl, phenyl andC₁-C₃-alkoxy, or R¹ is phenyl or naphthyl, where phenyl or naphthyl aresubstituted by 1, 2 or 3 substituents R¹⁻², the substituents R¹⁻² beingselected independently of one another from the group consisting ofhalogen, C₁-C₄ alkyl, dimethylamino, cyano, trifluoromethyl, 5- or6-membered heterocyclyl, 5- or 6-membered heteroaryl, C₁-C₃ alkoxy,phenyloxy or benzyloxy, or two substituents R¹⁻², together with thecarbon atoms to which they are attached, form a 1,3-benzodioxole or a1,4-benzodioxane, R² is hydrogen, R³ is hydrogen, amino, methylamino ordimethylamino, R⁴ is methyl, R⁵ is fluoro, chloro, trifluoromethyl,C₁-C₃ alkoxy, C₁-C₄ alkyl, phenyl or pyridyl, R⁶ is isopropyl,tert-butyl, isopentyl, cyclopentyl or cyclohexyl, n is a number 0, 1 or2, and, if n is 2, the radicals R⁵ can be identical or different, m is anumber 0, 1 or 2, and A is phenyl, naphthyl, pyridyl, thienyl,quinolinyl or isoquinolinyl.
 5. A compound according to claim 1,characterized in that R¹ is pyridyl, thienyl, furyl, quinolinyl orisoquinolinyl, where R¹ can be substituted by 0, 1 or 2 substituentsR¹⁻¹, the substituents R¹⁻¹ being selected independently of one anotherfrom the group consisting of fluoro, chloro, trifluoromethyl, C₁-C₄alkyl, phenyl and methoxy.
 6. A compound as claimed in any of claims 1to 4 according to claim 1, characterized in that R¹ is phenyl ornaphthyl, where phenyl or naphthyl are substituted by 1, 2 or 3substituents R¹⁻², the substituents R¹⁻² being selected independently ofone another from the group consisting of halogen, C₁-C₄ alkyl,dimethylamino, cyano, trifluoromethyl, 5- or 6-membered heterocyclyl, 5-or 6-membered heteroaryl, C₁-C₃ alkoxy, phenyloxy or benzyloxy, or twosubstituents R¹⁻², together with the carbon atoms to which they areattached, form a 1,3-benzodioxole or a 1,4-benzodioxane.
 7. A compoundaccording to claim 1, characterized in that R² is hydrogen.
 8. Acompound according to claim 1, characterized in that R³ is hydrogen oramino.
 9. A compound according to claim 1, characterized in that R⁴ ismethyl.
 10. A compound according to claim 1, characterized in that n isthe number zero.
 11. A compound as claimed according to claim 1,characterized in that n is the number 1, A is phenyl and R⁵ is fluoro,chloro, trifluoromethyl, alkoxy, C₁-C₄-alkyl, phenyl or pyridyl, R⁵being positioned meta or para to the linkage site of the phenyl ring.12. A compound according to claim 1, characterized in that R⁶ isC₃-C₆-alkyl or 3- to 6-membered cycloalkyl.
 13. A compound according toclaim 1, characterized in that m is the number zero.
 14. A compoundaccording to claim 1, characterized in that A is phenyl, naphthyl,pyridyl, thienyl, quinolinyl or isoquinolinyl.
 15. A process forpreparing a compound of formula (I) according to claim 1, characterizedin that [A] a compound of the formula

in which R² to R⁶, A and n are as defined in claim 1, is reacted with acompound of the formula

in which R¹ and m are as defined in claim 1, or [B] a compound of theformula

in which R³, R⁴ and R⁶ are as defined in claim 1, is reacted with acompound of the formula

in which R¹, R², R⁵, A, m and n are as defined in claim
 1. 16. Acompound of claim 1 for the treatment and/or prophylaxis of diseases.17. A medicinal product comprising at least one compound of claim 1 incombination with at least one pharmaceutically compatible,pharmaceutically acceptable carrier or other excipients.
 18. The use ofa compound of claim 1 for producing a medicinal product for thetreatment and/or prophylaxis of bacterial diseases.
 19. A medicinalproduct according to claim 17 for the treatment and/or prophylaxis ofbacterial infections.
 20. A method of controlling bacterial infectionsin people and animals by administering an antibacterially effectiveamount of at least one compound of claim 1.